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Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy 2.0

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: 31 October 2024 | Viewed by 12257

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Special Issue Editors

Dr. Gautam Sethi

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Guest Editor

Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
Interests: cancer; inflammation; transcription factors; vitamin; apoptosis
Special Issues, Collections and Topics in MDPI journals

Dr. Milad Ashrafizadeh

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Guest Editor

Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla, 34956 Istanbul, Turkey
Interests: cancer therapy; gene therapy; nanomedicine; non-coding RNAs; transcription factors

Special Issue Information

Dear Colleagues,

The activation of oncogenic transcription factors (NF-κB, STAT3, STAT5, AP-1, etc.) and proteins (Ras, Raf, Src, etc.) plays an important role in tumorigenesis. The mechanisms regulating the activation of these transcription factors and proteins are complex and constantly evolving. This Special Issue will explore the role of oncogenic transcription factors/proteins in carcinogenesis and highlight novel pharmacological strategies that can be used to target them, subsequently mitigating the processes of abnormal proliferation and survival of tumor cells.

Dr. Gautam Sethi
Dr. Milad Ashrafizadeh
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cancer
transcription factors
apoptosis
oncogenes
natural agents

Related Special Issue

Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy in Biomedicines (11 articles)

Published Papers (7 papers)

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Research

17 pages, 3348 KiB

Open AccessArticle

RAC1b Collaborates with TAp73α-SMAD4 Signaling to Induce Biglycan Expression and Inhibit Basal and TGF-β-Driven Cell Motility in Human Pancreatic Cancer

by Hendrik Ungefroren, Julissa Reimann, Björn Konukiewitz, Rüdiger Braun, Ulrich F. Wellner, Hendrik Lehnert and Jens-Uwe Marquardt

Biomedicines 2024, 12(1), 199; https://doi.org/10.3390/biomedicines12010199 - 16 Jan 2024

Viewed by 884

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer type characterized by a marked desmoplastic tumor stroma that is formed under the influence of transforming growth factor (TGF)-β. Data from mouse models of pancreatic cancer have revealed that transcriptionally active p73 (TAp73) impacts the TGF-β pathway through activation of Smad4 and secretion of biglycan (Bgn). However, whether this pathway also functions in human PDAC cells has not yet been studied. Here, we show that RNA interference-mediated silencing of TAp73 in PANC-1 cells strongly reduced the stimulatory effect of TGF-β1 on BGN. TAp73-mediated regulation of BGN, and inhibition of TGF-β signaling through a (Smad-independent) ERK pathway, are reminiscent of what we previously observed for the small GTPase, RAC1b, prompting us to hypothesize that in human PDAC cells TAp73 and RAC1b are part of the same tumor-suppressive pathway. Like TAp73, RAC1b induced SMAD4 protein and mRNA expression. Moreover, siRNA-mediated knockdown of RAC1b reduced TAp73 mRNA levels, while ectopic expression of RAC1b increased them. Inhibition of BGN synthesis or depletion of secreted BGN from the culture medium reproduced the promigratory effect of RAC1b or TAp73 silencing and was associated with increased basal and TGF-β1-dependent ERK activation. BGN also phenocopied the effects of RAC1b or TAp73 on the expression of downstream effectors, like the EMT markers E-cadherin, Vimentin and SNAIL, as well as on negative regulation of the ALK2-SMAD1/5 arm of TGF-β signaling. Collectively, we showed that tumor-suppressive TAp73-Smad4-Bgn signaling also operates in human cells and that RAC1b likely acts as an upstream activator of this pathway. Full article

(This article belongs to the Special Issue Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy 2.0)

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15 pages, 3595 KiB

Open AccessArticle

Methoxyhispolon Methyl Ether, a Hispolon Analog, Thwarts the SRC/STAT3/BCL-2 Axis to Provoke Human Triple-Negative Breast Cancer Cell Apoptosis In Vitro

by Chih-Pin Liao, Ya-Chu Hsieh, Chien-Hsing Lu, Wen-Chi Dai, Wei-Ting Yang, Kur-Ta Cheng, Modukuri V. Ramani, Gottumukkala V. Subbaraju and Chia-Che Chang

Biomedicines 2023, 11(10), 2742; https://doi.org/10.3390/biomedicines11102742 - 10 Oct 2023

Viewed by 793

Abstract

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with few treatment options. A promising TNBC treatment approach is targeting the oncogenic signaling pathways pivotal to TNBC initiation and progression. Deregulated activation of signal transducer and activator of transcription 3 (STAT3) is fundamental to driving TNBC malignant transformation, highlighting STAT3 as a promising TNBC therapeutic target. Methoxyhispolon Methyl Ether (MHME) is an analog of Hispolon, an anti-cancer polyphenol found in the medicinal mushroom Phellinus linteus. Still, MHME’s anti-cancer effects and mechanisms remain unknown. Herein, we present the first report about MHME’s anti-TNBC effect and its action mechanism. We first revealed that MHME is proapoptotic and cytotoxic against human TNBC cell lines HS578T, MDA-MB-231, and MDA-MB-463 and displayed a more potent cytotoxicity than Hispolon’s. Mechanistically, MHME suppressed both constitutive and interleukin 6 (IL-6)-induced activation of STAT3 represented by the extent of tyrosine 705-phosphorylated STAT3 (p-STAT3). Notably, MHME-evoked apoptosis and clonogenicity impairment were abrogated in TNBC cells overexpressing a dominant-active mutant of STAT3 (STAT3-C); supporting the blockade of STAT3 activation is an integral mechanism of MHME’s cytotoxic action on TNBC cells. Moreover, MHME downregulated BCL-2 in a STAT3-dependent manner, and TNBC cells overexpressing BCL-2 were refractory to MHME-induced apoptosis, indicating that BCL-2 downregulation is responsible for MHME’s proapoptotic effect on TNBC cells. Finally, MHME suppressed SRC activation, while v-src overexpression rescued p-STAT3 levels and downregulated apoptosis in MHME-treated TNBC cells. Collectively, we conclude that MHME provokes TNBC cell apoptosis through the blockade of the SRC/STAT3/BCL-2 pro-survival axis. Our findings suggest the potential of applying MHME as a TNBC chemotherapy agent. Full article

(This article belongs to the Special Issue Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy 2.0)

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16 pages, 7760 KiB

Open AccessArticle

Identification of SEC61G as a Diagnostic and Prognostic Biomarker in Oral Squamous Cell Carcinoma

by Shi-Long Zhang, Lei Chen, Lin-Lin Bu, Zi-Li Yu and Si-Rui Ma

Biomedicines 2023, 11(10), 2718; https://doi.org/10.3390/biomedicines11102718 - 06 Oct 2023

Viewed by 929

Abstract

Oral squamous cell carcinoma (OSCC) is a heterogeneous malignancy originating from the oral mucosal epithelium. Detecting novel biomarkers can offer crucial information on disease aggressiveness and expected clinical outcomes for individual patients. SEC61G, an aberrantly expressed gene in various cancers, has been associated with negative clinical outcomes. However, its expression and clinical significance in OSCC is still unclear. In the present study, we investigated the SEC61G expression level in OSCC using bioinformatic and immunohistochemical analyses. Additionally, our findings revealed a significant correlation between SEC61G expression and clinicopathological characteristics, as well as a worse prognosis in OSCC patients. Notably, flow cytometry analysis on patient samples revealed that SEC61G expression was also linked to decreased immune infiltration in OSCC patients. In conclusion, our study provides evidence supporting SEC61G’s role as a potential diagnostic, prognostic, and therapeutic marker in OSCC. Full article

(This article belongs to the Special Issue Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy 2.0)

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18 pages, 6401 KiB

Open AccessArticle

Development of Piperazine- and Oxazine-Linked Pyrimidines as p65 Subunit Binders of NF–κB in Human Breast Cancer Cells

by Akshay Ravish, Bhanuprakash C. Narasimhachar, Zhang Xi, Divakar Vishwanath, Arunkumar Mohan, Santosh L. Gaonkar, Paduvalahippe Gowdegowda Chandrashekara, Kwang Seok Ahn, Vijay Pandey, Peter E. Lobie and Basappa Basappa

Biomedicines 2023, 11(10), 2716; https://doi.org/10.3390/biomedicines11102716 - 06 Oct 2023

Cited by 1 | Viewed by 828

Abstract

Nuclear factor kappa B (NF–κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine– and piperazine–linked pyrimidines was developed as inhibitors of NF–κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine–pyrimidine and piperazine–pyrimidine derivatives, compounds 3a and 5b inhibited breast cancer cell (MCF–7) viability with an IC₅₀ value of 9.17 and 6.29 µM, respectively. In silico docking studies showed that the pyrimidine ring of 3a and the 4–methoxybenzyl thiol group of 5b could strongly bind the p65 subunit of NF–κB, with the binding energies −9.32 and −7.32 kcal mol⁻¹. Furthermore, compounds 3a and 5b inhibited NF–κB in MCF–7 breast cancer cells. In conclusion, we herein report newer structures that target NF–κB in BC cells. Full article

(This article belongs to the Special Issue Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy 2.0)

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24 pages, 14281 KiB

Open AccessArticle

Methyl-Thiol-Bridged Oxadiazole and Triazole Heterocycles as Inhibitors of NF-κB in Chronic Myelogenous Leukemia Cells

by Basappa Basappa, Young Yun Jung, Akshay Ravish, Zhang Xi, Ananda Swamynayaka, Mahendra Madegowda, Vijay Pandey, Peter E. Lobie, Gautam Sethi and Kwang Seok Ahn

Biomedicines 2023, 11(6), 1662; https://doi.org/10.3390/biomedicines11061662 - 08 Jun 2023

Cited by 2 | Viewed by 2456

Abstract

Nuclear factor kappa beta (NF-κB) is a transcriptional factor that plays a crucial role in regulating cancer cell proliferation. Therefore, the inhibition of NF-κB activity by small molecules may be beneficial in cancer therapy. In this report, methyl-thiol-bridged oxadiazole and triazole heterocycles were synthesized via click chemistry and it was observed that the lead structure, 2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-(4-methoxybenzyl)-1,3,4-oxadiazole (4c), reduced the viability of MCF-7 cells with an IC₅₀ value of 7.4 µM. Compound 4c also caused concentration-dependent loss of cell viability in chronic myelogenous leukemia (CML) cells. Furthermore, compound 4c inhibited the activation of NF-κB in human CML cells as observed by nuclear translocation and DNA binding assays. Functionally, compound 4c produced PARP cleavage and also suppressed expression of Bcl-2/xl, MMP-9, COX-2, survivin, as well as VEGF, resulting in apoptosis of CML cells. Moreover, ChIP assay showed that compound 4c decreased the binding of COX-2 to the p65 gene promoter. Detailed in silico analysis also indicated that compound 4c targeted NF-κB in CML cells. In conclusion, a novel structure bearing both triazole and oxadiazole moieties has been identified that can target NF-κB in CML cells and may constitute a potential novel drug candidate. Full article

(This article belongs to the Special Issue Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy 2.0)

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Graphical abstract

19 pages, 7627 KiB

Open AccessArticle

Nano-Zirconium Dioxide Catalyzed Multicomponent Synthesis of Bioactive Pyranopyrazoles That Target Cyclin Dependent Kinase 1 in Human Breast Cancer Cells

by Basappa Basappa, Lisha K. Poonacha, Zhang Xi, Divakar Vishwanath, Ji-Rui Yang, Omantheswara Nagaraja, Ananda Swamynayaka, Mahendra Madegowda, Arunachalam Chinnathambi, Sulaiman Ali Alharbi, Doddahosuru Mahadevappa Gurudatt, Vijay Pandey, Nanjundaswamy Shivananju, Kwang Seok Ahn, Gautam Sethi, Peter E. Lobie and Priya Babu Shubha

Biomedicines 2023, 11(1), 172; https://doi.org/10.3390/biomedicines11010172 - 10 Jan 2023

Cited by 4 | Viewed by 1977

Abstract

Small molecules are being used to inhibit cyclin dependent kinase (CDK) enzymes in cancer treatment. There is evidence that CDK is a drug-target for cancer therapy across many tumor types because it catalyzes the transfer of the terminal phosphate of ATP to a protein that acts as a substrate. Herein, the identification of pyranopyrazoles that were CDK inhibitors was attempted, whose synthesis was catalyzed by nano-zirconium dioxide via multicomponent reaction. Additionally, we performed an in-situ analysis of the intermediates of multicomponent reactions, for the first-time, which revealed that nano-zirconium dioxide stimulated the reaction, as estimated by Gibbs free energy calculations of spontaneity. Functionally, the novel pyranopyrazoles were tested for a loss of cell viability using human breast cancer cells (MCF-7). It was observed that compounds 5b and 5f effectively produced loss of viability of MCF-7 cells with IC₅₀ values of 17.83 and 23.79 µM, respectively. In vitro and in silico mode-of-action studies showed that pyranopyrazoles target CDK1 in human breast cancer cells, with lead compounds 5b and 5f having potent IC₅₀ values of 960 nM and 7.16 μM, respectively. Hence, the newly synthesized bioactive pyranopyrazoles could serve as better structures to develop CDK1 inhibitors against human breast cancer cells. Full article

(This article belongs to the Special Issue Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy 2.0)

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18 pages, 3481 KiB

Open AccessArticle

Andrographis Reverses Gemcitabine Resistance through Regulation of ERBB3 and Calcium Signaling Pathway in Pancreatic Ductal Adenocarcinoma

by Keisuke Okuno, Caiming Xu, Silvia Pascual-Sabater, Masanori Tokunaga, Tetsuji Takayama, Haiyong Han, Cristina Fillat, Yusuke Kinugasa and Ajay Goel

Biomedicines 2023, 11(1), 119; https://doi.org/10.3390/biomedicines11010119 - 03 Jan 2023

Cited by 3 | Viewed by 3304

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, primarily due to intrinsic or acquired resistance to chemotherapy, such as Gemcitabine (Gem). Naturally occurring botanicals, including Andrographis (Andro), can help enhance the anti-tumorigenic therapeutic efficacy of conventional chemotherapy through time-tested safety and cost-effectiveness. Accordingly, we hypothesized that Andro might reverse Gem resistance in PDAC. The critical regulatory pathways associated with Gem resistance in PDAC were identified by analyzing publicly available transcriptomic profiling and PDAC tissue specimens. A series of systematic in vitro experiments were performed using Gem-resistant (Gem-R) PDAC cells and patient-derived 3D-organoids to evaluate the Andro-mediated reversal of Gem resistance in PDAC. Transcriptomic profiling identified the calcium signaling pathway as a critical regulator of Gem-resistance (Fold enrichment: 2.8, p = 0.002). Within this pathway, high ERBB3 expression was significantly associated with poor prognosis in PDAC patients. The combination of Andro and Gem exhibited superior anti-cancer potential in Gem-R PDAC cells through potentiating cellular apoptosis. The combined treatment down-regulated ERBB3 and decreased intracellular calcium concentration in Gem-R PDAC cells. Finally, these findings were successfully interrogated in patient-derived 3D-organoids. In conclusion, we demonstrate novel evidence for Andro-mediated reversal of chemoresistance to Gem in PDAC cells through the regulation of ERBB3 and calcium signaling. Full article

(This article belongs to the Special Issue Targeting Transcription Factors and Oncogenic Proteins for Cancer Therapy 2.0)

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