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Open AccessEditorial

Targeting STAT3 and STAT5 in Cancer

by Elvin D. de Araujo, György M. Keserű, Patrick T. Gunning and Richard Moriggl

Cancers 2020, 12(8), 2002; https://doi.org/10.3390/cancers12082002 - 22 Jul 2020

Cited by 9 | Viewed by 4503

Abstract

Insights into the mutational landscape of the human cancer genome coding regions defined about 140 distinct cancer driver genes in 2013, which approximately doubled to 300 in 2018 following advances in systems cancer biology studies [...] Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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Research

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24 pages, 6946 KiB

Open AccessArticle

STAT5 is Expressed in CD34⁺/CD38⁻ Stem Cells and Serves as a Potential Molecular Target in Ph-Negative Myeloproliferative Neoplasms

by Emir Hadzijusufovic, Alexandra Keller, Daniela Berger, Georg Greiner, Bettina Wingelhofer, Nadine Witzeneder, Daniel Ivanov, Emmanuel Pecnard, Harini Nivarthi, Florian K. M. Schur, Yüksel Filik, Christoph Kornauth, Heidi A. Neubauer, Leonhard Müllauer, Gary Tin, Jisung Park, Elvin D. de Araujo, Patrick T. Gunning, Gregor Hoermann, Fabrice Gouilleux, Robert Kralovics, Richard Moriggl and Peter Valent Show full author list Hide full author list

Cancers 2020, 12(4), 1021; https://doi.org/10.3390/cancers12041021 - 21 Apr 2020

Cited by 14 | Viewed by 5258

Abstract

Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most patients, JAK2 V617F or CALR mutations are found and lead to activation of various downstream signaling cascades and [...] Read more.

Janus kinase 2 (JAK2) and signal transducer and activator of transcription-5 (STAT5) play a key role in the pathogenesis of myeloproliferative neoplasms (MPN). In most patients, JAK2 V617F or CALR mutations are found and lead to activation of various downstream signaling cascades and molecules, including STAT5. We examined the presence and distribution of phosphorylated (p) STAT5 in neoplastic cells in patients with MPN, including polycythemia vera (PV, n = 10), essential thrombocythemia (ET, n = 15) and primary myelofibrosis (PMF, n = 9), and in the JAK2 V617F-positive cell lines HEL and SET-2. As assessed by immunohistochemistry, MPN cells displayed pSTAT5 in all patients examined. Phosphorylated STAT5 was also detected in putative CD34⁺/CD38⁻ MPN stem cells (MPN-SC) by flow cytometry. Immunostaining experiments and Western blotting demonstrated pSTAT5 expression in both the cytoplasmic and nuclear compartment of MPN cells. Confirming previous studies, we also found that JAK2-targeting drugs counteract the expression of pSTAT5 and growth in HEL and SET-2 cells. Growth-inhibition of MPN cells was also induced by the STAT5-targeting drugs piceatannol, pimozide, AC-3-019 and AC-4-130. Together, we show that CD34⁺/CD38⁻ MPN-SC express pSTAT5 and that pSTAT5 is expressed in the nuclear and cytoplasmic compartment of MPN cells. Whether direct targeting of pSTAT5 in MPN-SC is efficacious in MPN patients remains unknown. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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17 pages, 3036 KiB

Open AccessArticle

STAT3 Mutation Is Associated with STAT3 Activation in CD30⁺ ALK⁻ ALCL

by Emma I. Andersson, Oscar Brück, Till Braun, Susanna Mannisto, Leena Saikko, Sonja Lagström, Pekka Ellonen, Sirpa Leppä, Marco Herling, Panu E. Kovanen and Satu Mustjoki

Cancers 2020, 12(3), 702; https://doi.org/10.3390/cancers12030702 - 16 Mar 2020

Cited by 19 | Viewed by 4490

Abstract

Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to [...] Read more.

Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK⁺ ALCL, 38% of ALK⁻ ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK^- ALCL (15%). Concurrent mutations were found in all subgroups except ALK⁺ ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30⁺ phenotype representing primarily ALK⁻ ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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19 pages, 3611 KiB

Open AccessArticle

mTOR and STAT3 Pathway Hyper-Activation is Associated with Elevated Interleukin-6 Levels in Patients with Shwachman-Diamond Syndrome: Further Evidence of Lymphoid Lineage Impairment

by Antonio Vella, Elisabetta D’Aversa, Martina Api, Giulia Breveglieri, Marisole Allegri, Alice Giacomazzi, Elena Marinelli Busilacchi, Benedetta Fabrizzi, Tiziana Cestari, Claudio Sorio, Gloria Bedini, Giovanna D’Amico, Vincenzo Bronte, Antonella Poloni, Antonio Benedetti, Chiara Bovo, Seth J. Corey, Monica Borgatti, Marco Cipolli and Valentino Bezzerri

Cancers 2020, 12(3), 597; https://doi.org/10.3390/cancers12030597 - 5 Mar 2020

Cited by 9 | Viewed by 4588

Abstract

Shwachman–Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome, resulting in neutropenia and a risk of myeloid neoplasia. A mutation in a ribosome maturation factor accounts for almost all of the cases. Lymphoid involvement in SDS has not been well characterized. [...] Read more.

Shwachman–Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome, resulting in neutropenia and a risk of myeloid neoplasia. A mutation in a ribosome maturation factor accounts for almost all of the cases. Lymphoid involvement in SDS has not been well characterized. We recently reported that lymphocyte subpopulations are reduced in SDS patients. We have also shown that the mTOR-STAT3 pathway is hyper-activated in SDS myeloid cell populations. Here we show that mTOR-STAT3 signaling is markedly upregulated in the lymphoid compartment of SDS patients. Furthermore, our data reveal elevated IL-6 levels in cellular supernatants obtained from lymphoblasts, bone marrow mononuclear and mesenchymal stromal cells, and plasma samples obtained from a cohort of 10 patients. Of note, everolimus-mediated inhibition of mTOR signaling is associated with basal state of phosphorylated STAT3. Finally, inhibition of mTOR-STAT3 pathway activation leads to normalization of IL-6 expression in SDS cells. Altogether, our data strengthen the hypothesis that SDS affects both lymphoid and myeloid blood compartment and suggest everolimus as a potential therapeutic agent to reduce excessive mTOR-STAT3 activation in SDS. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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17 pages, 2439 KiB

Open AccessFeature PaperArticle

A Novel Inhibitor of STAT5 Signaling Overcomes Chemotherapy Resistance in Myeloid Leukemia Cells

by Marie Brachet-Botineau, Margaux Deynoux, Nicolas Vallet, Marion Polomski, Ludovic Juen, Olivier Hérault, Frédéric Mazurier, Marie-Claude Viaud-Massuard, Gildas Prié and Fabrice Gouilleux

Cancers 2019, 11(12), 2043; https://doi.org/10.3390/cancers11122043 - 17 Dec 2019

Cited by 17 | Viewed by 4303

Abstract

Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are crucial downstream effectors of tyrosine kinase oncogenes (TKO) such as BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML). Both proteins have been shown to promote [...] Read more.

Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are crucial downstream effectors of tyrosine kinase oncogenes (TKO) such as BCR-ABL in chronic myeloid leukemia (CML) and FLT3-ITD in acute myeloid leukemia (AML). Both proteins have been shown to promote the resistance of CML cells to tyrosine kinase inhibitors (TKI) such as imatinib mesylate (IM). We recently synthesized and discovered a new inhibitor (17f) with promising antileukemic activity. 17f selectively inhibits STAT5 signaling in CML and AML cells by interfering with the phosphorylation and transcriptional activity of these proteins. In this study, the effects of 17f were evaluated on CML and AML cell lines that respectively acquired resistance to IM and cytarabine (Ara-C), a conventional therapeutic agent used in AML treatment. We showed that 17f strongly inhibits the growth and survival of resistant CML and AML cells when associated with IM or Ara-C. We also obtained evidence that 17f inhibits STAT5B but not STAT5A protein expression in resistant CML and AML cells. Furthermore, we demonstrated that 17f also targets oncogenic STAT5B N642H mutant in transformed hematopoietic cells. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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18 pages, 3190 KiB

Open AccessArticle

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

by Linus Wahnschaffe, Till Braun, Sanna Timonen, Anil K. Giri, Alexandra Schrader, Prerana Wagle, Henrikki Almusa, Patricia Johansson, Dorine Bellanger, Cristina López, Claudia Haferlach, Marc-Henri Stern, Jan Dürig, Reiner Siebert, Satu Mustjoki, Tero Aittokallio and Marco Herling

Cancers 2019, 11(12), 1833; https://doi.org/10.3390/cancers11121833 - 21 Nov 2019

Cited by 38 | Viewed by 6037

Abstract

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed [...] Read more.

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed in rather small cohorts. Therefore, we conducted—via a primary-data based pipeline—a meta-analysis that re-evaluated the genomic landscape of T-PLL. It included all available data sets with sequence information on JAK or STAT gene loci in 275 T-PLL. We eliminated overlapping cases and determined a cumulative rate of 62.1% of cases with mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants (SNVs), with missense mutations in the SH2 or pseudokinase domains as most prevalent. Importantly, these lesions were predominantly subclonal. We did not detect any strong association between mutations of a JAK or STAT gene with clinical characteristics. Irrespective of the presence of gain-of-function (GOF) SNVs, basal phosphorylation of STAT5B was elevated in all analyzed T-PLL. Fittingly, a significant proportion of genes encoding for potential negative regulators of STAT5B showed genomic losses (in 71.4% of T-PLL in total, in 68.4% of T-PLL without any JAK or STAT mutations). They included DUSP4, CD45, TCPTP, SHP1, SOCS1, SOCS3, and HDAC9. Overall, considering such losses of negative regulators and the GOF mutations in JAK and STAT genes, a total of 89.8% of T-PLL revealed a genomic aberration potentially explaining enhanced STAT5B activity. In essence, we present a comprehensive meta-analysis on the highly prevalent genomic lesions that affect genes encoding JAK/STAT signaling components. This provides an overview of possible modes of activation of this pathway in a large cohort of T-PLL. In light of new advances in JAK/STAT inhibitor development, we also outline translational contexts for harnessing active JAK/STAT signaling, which has emerged as a ‘secondary’ hallmark of T-PLL. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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20 pages, 4485 KiB

Open AccessEditor’s ChoiceArticle

STAT3 Activity Promotes Programmed-Death Ligand 1 Expression and Suppresses Immune Responses in Breast Cancer

by Ioannis Zerdes, Majken Wallerius, Emmanouil G. Sifakis, Tatjana Wallmann, Stina Betts, Margarita Bartish, Nikolaos Tsesmetzis, Nicholas P. Tobin, Christos Coucoravas, Jonas Bergh, George Z. Rassidakis, Charlotte Rolny and Theodoros Foukakis

Cancers 2019, 11(10), 1479; https://doi.org/10.3390/cancers11101479 - 1 Oct 2019

Cited by 69 | Viewed by 6903

Abstract

Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and [...] Read more.

Signal transducer and activator of transcription 3 (STAT3) is an oncogene and multifaceted transcription factor involved in multiple cellular functions. Its role in modifying anti-tumor immunity has been recently recognized. In this study, the biologic effects of STAT3 on immune checkpoint expression and anti-tumor responses were investigated in breast cancer (BC). A transcriptional signature of phosphorylated STAT3 was positively correlated with PD-L1 expression in two independent cohorts of early BC. Pharmacologic inhibition and gene silencing of STAT3 led to decreased Programmed Death Ligand 1 (PD-L1) expression levels in vitro, and resulted as well in reduction of tumor growth and decreased metastatic dissemination in a mammary carcinoma mouse model. The hampering of tumor progression was correlated to an anti-tumoral macrophage phenotype and accumulation of natural-killer cells, but also in reduced accrual of cytotoxic lymphocytes. In human BC, pro-tumoral macrophages correlated to PD-L1 expression, proliferation status and higher grade of malignancy, indicating a subset of patients with immunosuppressive properties. In conclusion, this study provides evidence for STAT3-mediated regulation of PD-L1 and modulation of immune microenvironment in BC. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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25 pages, 5331 KiB

Open AccessArticle

Hepatic Stress Response in HCV Infection Promotes STAT3-Mediated Inhibition of HNF4A-miR-122 Feedback Loop in Liver Fibrosis and Cancer Progression

by Yucel Aydin, Ramazan Kurt, Kyoungsub Song, Dong Lin, Hanadi Osman, Brady Youngquist, John W. Scott, Nathan J. Shores, Paul Thevenot, Ari Cohen and Srikanta Dash

Cancers 2019, 11(10), 1407; https://doi.org/10.3390/cancers11101407 - 20 Sep 2019

Cited by 31 | Viewed by 5270

Abstract

Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a [...] Read more.

Hepatitis C virus (HCV) infection compromises the natural defense mechanisms of the liver leading to a progressive end stage disease such as cirrhosis and hepatocellular carcinoma (HCC). The hepatic stress response generated due to viral replication in the endoplasmic reticulum (ER) undergoes a stepwise transition from adaptive to pro-survival signaling to improve host cell survival and liver disease progression. The minute details of hepatic pro-survival unfolded protein response (UPR) signaling that contribute to HCC development in cirrhosis are unknown. This study shows that the UPR sensor, the protein kinase RNA-like ER kinase (PERK), mediates the pro-survival signaling through nuclear factor erythroid 2-related factor 2 (NRF2)-mediated signal transducer and activator of transcription 3 (STAT3) activation in a persistent HCV infection model of Huh-7.5 liver cells. The NRF2-mediated STAT3 activation in persistently infected HCV cell culture model resulted in the decreased expression of hepatocyte nuclear factor 4 alpha (HNF4A), a major liver-specific transcription factor. The stress-induced inhibition of HNF4A expression resulted in a significant reduction of liver-specific microRNA-122 (miR-122) transcription. It was found that the reversal of hepatic adaptive pro-survival signaling and restoration of miR-122 level was more efficient by interferon (IFN)-based antiviral treatment than direct-acting antivirals (DAAs). To test whether miR-122 levels could be utilized as a biomarker of hepatic adaptive stress response in HCV infection, serum miR-122 level was measured among healthy controls, and chronic HCV patients with or without cirrhosis. Our data show that serum miR-122 expression level remained undetectable in most of the patients with cirrhosis (stage IV fibrosis), suggesting that the pro-survival UPR signaling increases the risk of HCC through STAT3-mediated suppression of miR-122. In conclusion, our data indicate that hepatic pro-survival UPR signaling suppresses the liver-specific HNF4A and its downstream target miR-122 in cirrhosis. These results provide an explanation as to why cirrhosis is a risk factor for the development of HCC in chronic HCV infection. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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25 pages, 5122 KiB

Open AccessFeature PaperArticle

STAT5a/b Deficiency Delays, but does not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice

by Florence Boutillon, Natascha Pigat, Lucila Sackmann Sala, Edouard Reyes-Gomez, Richard Moriggl, Jacques-Emmanuel Guidotti and Vincent Goffin

Cancers 2019, 11(7), 929; https://doi.org/10.3390/cancers11070929 - 2 Jul 2019

Cited by 13 | Viewed by 3995

Abstract

The canonical prolactin (PRL) Signal Transducer and Activator of Transcription (STAT) 5 pathway has been suggested to contribute to human prostate tumorigenesis via an autocrine/paracrine mechanism. The probasin (Pb)-PRL transgenic mouse models this mechanism by overexpressing PRL specifically in the prostate epithelium leading [...] Read more.

The canonical prolactin (PRL) Signal Transducer and Activator of Transcription (STAT) 5 pathway has been suggested to contribute to human prostate tumorigenesis via an autocrine/paracrine mechanism. The probasin (Pb)-PRL transgenic mouse models this mechanism by overexpressing PRL specifically in the prostate epithelium leading to strong STAT5 activation in luminal cells. These mice exhibit hypertrophic prostates harboring various pre-neoplastic lesions that aggravate with age and accumulation of castration-resistant stem/progenitor cells. As STAT5 signaling is largely predominant over other classical PRL-triggered pathways in Pb-PRL prostates, we reasoned that Pb-Cre recombinase-driven genetic deletion of a floxed Stat5a/b locus should prevent prostate tumorigenesis in so-called Pb-PRL^ΔSTAT5 mice. Anterior and dorsal prostate lobes displayed the highest Stat5a/b deletion efficiency with no overt compensatory activation of other PRLR signaling cascade at 6 months of age; hence the development of tumor hallmarks was markedly reduced. Stat5a/b deletion also reversed the accumulation of stem/progenitor cells, indicating that STAT5 signaling regulates prostate epithelial cell hierarchy. Interestingly, ERK1/2 and AKT, but not STAT3 and androgen signaling, emerged as escape mechanisms leading to delayed tumor development in aged Pb-PRL^ΔSTAT5 mice. Unexpectedly, we found that Pb-PRL prostates spontaneously exhibited age-dependent decline of STAT5 signaling, also to the benefit of AKT and ERK1/2 signaling. As a consequence, both Pb-PRL and Pb-PRL^ΔSTAT5 mice ultimately displayed similar pathological prostate phenotypes at 18 months of age. This preclinical study provides insight on STAT5-dependent mechanisms of PRL-induced prostate tumorigenesis and alternative pathways bypassing STAT5 signaling down-regulation upon prostate neoplasia progression. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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22 pages, 5409 KiB

Open AccessArticle

Therapeutic Targeting of Stat3 Using Lipopolyplex Nanoparticle-Formulated siRNA in a Syngeneic Orthotopic Mouse Glioma Model

by Benedikt Linder, Ulrike Weirauch, Alexander Ewe, Anja Uhmann, Volker Seifert, Michel Mittelbronn, Patrick N. Harter, Achim Aigner and Donat Kögel

Cancers 2019, 11(3), 333; https://doi.org/10.3390/cancers11030333 - 8 Mar 2019

Cited by 25 | Viewed by 5381

Abstract

Glioblastoma (GBM), WHO grade IV, is the most aggressive primary brain tumor in adults. The median survival time using standard therapy is only 12–15 months with a 5-year survival rate of around 5%. Thus, new and effective treatment modalities are of significant importance. [...] Read more.

Glioblastoma (GBM), WHO grade IV, is the most aggressive primary brain tumor in adults. The median survival time using standard therapy is only 12–15 months with a 5-year survival rate of around 5%. Thus, new and effective treatment modalities are of significant importance. Signal transducer and activator of transcription 3 (Stat3) is a key signaling protein driving major hallmarks of cancer and represents a promising target for the development of targeted glioblastoma therapies. Here we present data showing that the therapeutic application of siRNAs, formulated in nanoscale lipopolyplexes (LPP) based on polyethylenimine (PEI) and the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), represents a promising new approach to target Stat3 in glioma. We demonstrate that the LPP-mediated delivery of siRNA mediates efficient knockdown of Stat3, suppresses Stat3 activity and limits cell growth in murine (Tu2449) and human (U87, Mz18) glioma cells in vitro. In a therapeutic setting, intracranial application of the siRNA-containing LPP leads to knockdown of STAT3 target gene expression, decreased tumor growth and significantly prolonged survival in Tu2449 glioma-bearing mice compared to negative control-treated animals. This is a proof-of-concept study introducing PEI-based lipopolyplexes as an efficient strategy for therapeutically targeting oncoproteins with otherwise limited druggability. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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14 pages, 2570 KiB

Open AccessArticle

Decoration of Anti-CD38 on Nanoparticles Carrying a STAT3 Inhibitor Can Improve the Therapeutic Efficacy Against Myeloma

by Yung-Hsing Huang, Mohammad Reza Vakili, Ommoleila Molavi, Yuen Morrissey, Chengsheng Wu, Igor Paiva, Amir Hasan Soleimani, Forugh Sanaee, Afsaneh Lavasanifar and Raymond Lai

Cancers 2019, 11(2), 248; https://doi.org/10.3390/cancers11020248 - 20 Feb 2019

Cited by 31 | Viewed by 5388

Abstract

STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our [...] Read more.

STAT3 is an oncoprotein which has been shown to contribute to drug resistance in multiple myeloma (MM). Nonetheless, the clinical utility of STAT3 inhibitors in treating MM has been limited, partly related to some of their pharmacologic properties. To overcome these challenges, our group had previously packaged STAT3 inhibitors using a novel formulation of nanoparticles (NP) and found encouraging results. In this study, we aimed to further improve the pharmacologic properties of these NP by decorating them with monoclonal anti-CD38 antibodies. NP loaded with S3I-1757 (a STAT3 inhibitor), labeled as S3I-NP, were generated. S3I-NP decorated with anti-CD38 (labeled as CD38-S3I-NP) were found to have a similar nanoparticular size, drug encapsulation, and loading as S3I-NP. The release of S3I-1757 at 24 h was also similar between the two formulations. Using Cy5.5 labeling of the NP, we found that the decoration of anti-CD38 on these NP significantly increased the cellular uptake by two MM cell lines (p < 0.001). Accordingly, CD38-S3I-NP showed a significantly lower inhibitory concentration at 50% (IC50) compared to S3I-NP in two IL6-stimulated MM cell lines (p < 0.001). In a xenograft mouse model, CD38-S3I-NP significantly reduced the tumor size by 4-fold compared to S3I-NP on day 12 after drug administration (p = 0.006). The efficacy of CD38-S3I-NP in suppressing STAT3 phosphorylation in the xenografts was confirmed by using immunocytochemistry and Western blot analysis. In conclusion, our study suggests that the decoration of anti-CD38 on NP loaded with STAT3 inhibitors can further improve their therapeutic effects against MM. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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Review

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48 pages, 2713 KiB

Open AccessEditor’s ChoiceReview

Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers

by Marie Brachet-Botineau, Marion Polomski, Heidi A. Neubauer, Ludovic Juen, Damien Hédou, Marie-Claude Viaud-Massuard, Gildas Prié and Fabrice Gouilleux

Cancers 2020, 12(1), 240; https://doi.org/10.3390/cancers12010240 - 18 Jan 2020

Cited by 52 | Viewed by 8877

Abstract

Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 [...] Read more.

Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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26 pages, 1098 KiB

Open AccessEditor’s ChoiceReview

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

by Chin-Jui Wu, Vignesh Sundararajan, Bor-Ching Sheu, Ruby Yun-Ju Huang and Lin-Hung Wei

Cancers 2020, 12(1), 24; https://doi.org/10.3390/cancers12010024 - 19 Dec 2019

Cited by 57 | Viewed by 8399

Abstract

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance [...] Read more.

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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27 pages, 2661 KiB

Open AccessReview

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

by Gaëtan Jego, François Hermetet, François Girodon and Carmen Garrido

Cancers 2020, 12(1), 21; https://doi.org/10.3390/cancers12010021 - 19 Dec 2019

Cited by 26 | Viewed by 6604

Abstract

While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. [...] Read more.

While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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16 pages, 1066 KiB

Open AccessReview

Companion Animals as Models for Inhibition of STAT3 and STAT5

by Matthias Kieslinger, Alexander Swoboda, Nina Kramer, Barbara Pratscher, Birgitt Wolfesberger and Iwan A. Burgener

Cancers 2019, 11(12), 2035; https://doi.org/10.3390/cancers11122035 - 17 Dec 2019

Cited by 4 | Viewed by 5094

Abstract

The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases [...] Read more.

The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases is of high therapeutic relevance. Given the high failure rate of drugs at the clinical trial phase (i.e., around 90%), there is a critical need for additional clinically relevant animal models. Companion animals like cats and dogs display chronic inflammatory or neoplastic diseases that closely resemble the human counterpart. Cat and dog patients can also be treated with clinically approved inhibitors or, if ethics and drug safety studies allow, pilot studies can be conducted using, e.g., inhibitors of the evolutionary conserved JAK-STAT pathway. The incidence by which different types of cancers occur in companion animals as well as mechanisms of disease are unique between humans and companion animals, where one can learn from each other. Taking advantage of this situation, existing inhibitors of known oncogenic STAT3/5 or JAK kinase signaling pathways can be studied in the context of rare human diseases, benefitting both, the development of drugs for human use and their application in veterinary medicine. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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16 pages, 2122 KiB

Open AccessReview

Direct Targeting Options for STAT3 and STAT5 in Cancer

by Anna Orlova, Christina Wagner, Elvin D. de Araujo, Dávid Bajusz, Heidi A. Neubauer, Marco Herling, Patrick T. Gunning, György M. Keserű and Richard Moriggl

Cancers 2019, 11(12), 1930; https://doi.org/10.3390/cancers11121930 - 3 Dec 2019

Cited by 65 | Viewed by 8300

Abstract

Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is [...] Read more.

Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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22 pages, 1450 KiB

Open AccessReview

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

by Grégory Verdeil, Toby Lawrence, Anne-Marie Schmitt-Verhulst and Nathalie Auphan-Anezin

Cancers 2019, 11(12), 1832; https://doi.org/10.3390/cancers11121832 - 21 Nov 2019

Cited by 42 | Viewed by 8498

Abstract

Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, [...] Read more.

Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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17 pages, 1351 KiB

Open AccessReview

Nucleocytoplasmic Shuttling of STATs. A Target for Intervention?

by Sabrina Ernst and Gerhard Müller-Newen

Cancers 2019, 11(11), 1815; https://doi.org/10.3390/cancers11111815 - 19 Nov 2019

Cited by 10 | Viewed by 4330

Abstract

Signal transducer and activator of transcription (STAT) proteins are transcription factors that in the latent state are located predominantly in the cytoplasm. Activation of STATs through phosphorylation of a single tyrosine residue results in nuclear translocation. The requirement of tyrosine phosphorylation for nuclear [...] Read more.

Signal transducer and activator of transcription (STAT) proteins are transcription factors that in the latent state are located predominantly in the cytoplasm. Activation of STATs through phosphorylation of a single tyrosine residue results in nuclear translocation. The requirement of tyrosine phosphorylation for nuclear accumulation is shared by all STAT family members but mechanisms of nuclear translocation vary between different STATs. These differences offer opportunities for specific intervention. To achieve this, the molecular mechanisms of nucleocytoplasmic shuttling of STATs need to be understood in more detail. In this review we will give an overview on the various aspects of nucleocytoplasmic shuttling of latent and activated STATs with a special focus on STAT3 and STAT5. Potential targets for cancer treatment will be identified and discussed. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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21 pages, 989 KiB

Open AccessReview

Structural Implications of STAT3 and STAT5 SH2 Domain Mutations

by Elvin D. de Araujo, Anna Orlova, Heidi A. Neubauer, Dávid Bajusz, Hyuk-Soo Seo, Sirano Dhe-Paganon, György M. Keserű, Richard Moriggl and Patrick T. Gunning

Cancers 2019, 11(11), 1757; https://doi.org/10.3390/cancers11111757 - 8 Nov 2019

Cited by 50 | Viewed by 6997

Abstract

Src Homology 2 (SH2) domains arose within metazoan signaling pathways and are involved in protein regulation of multiple pleiotropic cascades. In signal transducer and activator of transcription (STAT) proteins, SH2 domain interactions are critical for molecular activation and nuclear accumulation of phosphorylated STAT [...] Read more.

Src Homology 2 (SH2) domains arose within metazoan signaling pathways and are involved in protein regulation of multiple pleiotropic cascades. In signal transducer and activator of transcription (STAT) proteins, SH2 domain interactions are critical for molecular activation and nuclear accumulation of phosphorylated STAT dimers to drive transcription. Sequencing analysis of patient samples has revealed the SH2 domain as a hotspot in the mutational landscape of STAT proteins although the functional impact for the vast majority of these mutations remains poorly characterized. Despite several well resolved structures for SH2 domain-containing proteins, structural data regarding the distinctive STAT-type SH2 domain is limited. Here, we review the unique features of STAT-type SH2 domains in the context of all currently reported STAT3 and STAT5 SH2 domain clinical mutations. The genetic volatility of specific regions in the SH2 domain can result in either activating or deactivating mutations at the same site in the domain, underscoring the delicate evolutionary balance of wild type STAT structural motifs in maintaining precise levels of cellular activity. Understanding the molecular and biophysical impact of these disease-associated mutations can uncover convergent mechanisms of action for mutations localized within the STAT SH2 domain to facilitate the development of targeted therapeutic interventions. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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22 pages, 1491 KiB

Open AccessReview

ADAM17 Activity and IL-6 Trans-Signaling in Inflammation and Cancer

by Neele Schumacher and Stefan Rose-John

Cancers 2019, 11(11), 1736; https://doi.org/10.3390/cancers11111736 - 5 Nov 2019

Cited by 69 | Viewed by 7942

Abstract

All ligands of the epidermal growth factor receptor (EGF-R) are transmembrane proteins, which need to be proteolytically cleaved in order to be systemically active. The major protease responsible for this cleavage is the membrane metalloprotease ADAM17, which also has been implicated in cleavage [...] Read more.

All ligands of the epidermal growth factor receptor (EGF-R) are transmembrane proteins, which need to be proteolytically cleaved in order to be systemically active. The major protease responsible for this cleavage is the membrane metalloprotease ADAM17, which also has been implicated in cleavage of TNFα and interleukin-6 (IL-6) receptor. It has been recently shown that in the absence of ADAM17, the main protease for EGF-R ligand processing, colon cancer formation is largely abrogated. Intriguingly, colon cancer formation depends on EGF-R activity on myeloid cells rather than on intestinal epithelial cells. A major activity of EGF-R on myeloid cells is the stimulation of IL-6 synthesis. Subsequently, IL-6 together with the ADAM17 shed soluble IL-6 receptor acts on intestinal epithelial cells via IL-6 trans-signaling to induce colon cancer formation, which can be blocked by the inhibitor of IL-6 trans-signaling, sgp130Fc. Blockade of IL-6 trans-signaling therefore offers a new therapeutic window downstream of the EGF-R for the treatment of colon cancer and possibly of other EGF-R related neoplastic diseases. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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18 pages, 621 KiB

Open AccessReview

TYK2: An Upstream Kinase of STATs in Cancer

by Katharina Wöss, Natalija Simonović, Birgit Strobl, Sabine Macho-Maschler and Mathias Müller

Cancers 2019, 11(11), 1728; https://doi.org/10.3390/cancers11111728 - 5 Nov 2019

Cited by 43 | Viewed by 7114

Abstract

In this review we concentrate on the recent findings describing the oncogenic potential of the protein tyrosine kinase 2 (TYK2). The overview on the current understanding of TYK2 functions in cytokine responses and carcinogenesis focusses on the activation of the signal transducers and [...] Read more.

In this review we concentrate on the recent findings describing the oncogenic potential of the protein tyrosine kinase 2 (TYK2). The overview on the current understanding of TYK2 functions in cytokine responses and carcinogenesis focusses on the activation of the signal transducers and activators of transcription (STAT) 3 and 5. Insight gained from loss-of-function (LOF) gene-modified mice and human patients homozygous for Tyk2/TYK2-mutated alleles established the central role in immunological and inflammatory responses. For the description of physiological TYK2 structure/function relationships in cytokine signaling and of overarching molecular and pathologic properties in carcinogenesis, we mainly refer to the most recent reviews. Dysregulated TYK2 activation, aberrant TYK2 protein levels, and gain-of-function (GOF) TYK2 mutations are found in various cancers. We discuss the molecular consequences thereof and briefly describe the molecular means to counteract TYK2 activity under (patho-)physiological conditions by cellular effectors and by pharmacological intervention. For the role of TYK2 in tumor immune-surveillance we refer to the recent Special Issue of Cancers “JAK-STAT Signaling Pathway in Cancer”. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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29 pages, 2184 KiB

Open AccessReview

Balancing STAT Activity as a Therapeutic Strategy

by Kelsey L. Polak, Noah M. Chernosky, Jacob M. Smigiel, Ilaria Tamagno and Mark W. Jackson

Cancers 2019, 11(11), 1716; https://doi.org/10.3390/cancers11111716 - 3 Nov 2019

Cited by 23 | Viewed by 6360

Abstract

Driven by dysregulated IL-6 family member cytokine signaling in the tumor microenvironment (TME), aberrant signal transducer and activator of transcription (STAT3) and (STAT5) activation have been identified as key contributors to tumorigenesis. Following transformation, persistent STAT3 activation drives the emergence of mesenchymal/cancer-stem cell [...] Read more.

Driven by dysregulated IL-6 family member cytokine signaling in the tumor microenvironment (TME), aberrant signal transducer and activator of transcription (STAT3) and (STAT5) activation have been identified as key contributors to tumorigenesis. Following transformation, persistent STAT3 activation drives the emergence of mesenchymal/cancer-stem cell (CSC) properties, important determinants of metastatic potential and therapy failure. Moreover, STAT3 signaling within tumor-associated macrophages and neutrophils drives secretion of factors that facilitate metastasis and suppress immune cell function. Persistent STAT5 activation is responsible for cancer cell maintenance through suppression of apoptosis and tumor suppressor signaling. Furthermore, STAT5-mediated CD4+/CD25+ regulatory T cells (T_regs) have been implicated in suppression of immunosurveillance. We discuss these roles for STAT3 and STAT5, and weigh the attractiveness of different modes of targeting each cancer therapy. Moreover, we discuss how anti-tumorigenic STATs, including STAT1 and STAT2, may be leveraged to suppress the pro-tumorigenic functions of STAT3/STAT5 signaling. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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18 pages, 1809 KiB

Open AccessReview

Targeting STAT3 in Cancer with Nucleotide Therapeutics

by Yue-Ting K. Lau, Malini Ramaiyer, Daniel E. Johnson and Jennifer R. Grandis

Cancers 2019, 11(11), 1681; https://doi.org/10.3390/cancers11111681 - 29 Oct 2019

Cited by 40 | Viewed by 7263

Abstract

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an “undruggable” target for therapy; thus, much research has focused on targeting [...] Read more.

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an “undruggable” target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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22 pages, 1234 KiB

Open AccessReview

STAT3 and STAT5 Targeting for Simultaneous Management of Melanoma and Autoimmune Diseases

by Stella Logotheti and Brigitte M. Pützer

Cancers 2019, 11(10), 1448; https://doi.org/10.3390/cancers11101448 - 27 Sep 2019

Cited by 23 | Viewed by 5439

Abstract

Melanoma is a skin cancer which can become metastatic, drug-refractory, and lethal if managed late or inappropriately. An increasing number of melanoma patients exhibits autoimmune diseases, either as pre-existing conditions or as sequelae of immune-based anti-melanoma therapies, which complicate patient management and raise [...] Read more.

Melanoma is a skin cancer which can become metastatic, drug-refractory, and lethal if managed late or inappropriately. An increasing number of melanoma patients exhibits autoimmune diseases, either as pre-existing conditions or as sequelae of immune-based anti-melanoma therapies, which complicate patient management and raise the need for more personalized treatments. STAT3 and/or STAT5 cascades are commonly activated during melanoma progression and mediate the metastatic effects of key oncogenic factors. Deactivation of these cascades enhances antitumor-immune responses, is efficient against metastatic melanoma in the preclinical setting and emerges as a promising targeting strategy, especially for patients resistant to immunotherapies. In the light of the recent realization that cancer and autoimmune diseases share common mechanisms of immune dysregulation, we suggest that the systemic delivery of STAT3 or STAT5 inhibitors could simultaneously target both, melanoma and associated autoimmune diseases, thereby decreasing the overall disease burden and improving quality of life of this patient subpopulation. Herein, we review the recent advances of STAT3 and STAT5 targeting in melanoma, explore which autoimmune diseases are causatively linked to STAT3 and/or STAT5 signaling, and propose that these patients may particularly benefit from treatment with STAT3/STAT5 inhibitors. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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19 pages, 937 KiB

Open AccessReview

STAT3 and STAT5 Activation in Solid Cancers

by Sebastian Igelmann, Heidi A. Neubauer and Gerardo Ferbeyre

Cancers 2019, 11(10), 1428; https://doi.org/10.3390/cancers11101428 - 25 Sep 2019

Cited by 78 | Viewed by 8316

Abstract

The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We [...] Read more.

The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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24 pages, 447 KiB

Open AccessEditor’s ChoiceReview

STAT3, a Master Regulator of Anti-Tumor Immune Response

by Cédric Rébé and François Ghiringhelli

Cancers 2019, 11(9), 1280; https://doi.org/10.3390/cancers11091280 - 30 Aug 2019

Cited by 86 | Viewed by 8480

Abstract

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways [...] Read more.

Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g., by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors. Full article

(This article belongs to the Special Issue Targeting STAT3 and STAT5 in Cancer)

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