Life | Topical Collection : Tumor Progression, Microenvironments, and Therapeutics

2022

Jump to: 2021

14 pages, 9264 KiB

Open AccessArticle

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation in BNCT of Brain-Tumor-Model Rats—Ex Vivo Imaging of BPA Using MALDI Mass Spectrometry Imaging

by Sachie Kusaka, Yumi Miyake, Yugo Tokumaru, Yuri Morizane, Shingo Tamaki, Yoko Akiyama, Fuminobu Sato and Isao Murata

Life 2022, 12(11), 1786; https://doi.org/10.3390/life12111786 - 4 Nov 2022

Cited by 2 | Viewed by 2060

Abstract

The blood–brain barrier (BBB) is likely to be intact during the early stages of brain metastatic melanoma development, and thereby inhibits sufficient drug delivery into the metastatic lesions. Our laboratory has been developing a system for boron drug delivery to brain cells via [...] Read more.

The blood–brain barrier (BBB) is likely to be intact during the early stages of brain metastatic melanoma development, and thereby inhibits sufficient drug delivery into the metastatic lesions. Our laboratory has been developing a system for boron drug delivery to brain cells via cerebrospinal fluid (CSF) as a viable pathway to circumvent the BBB in boron neutron capture therapy (BNCT). BNCT is a cell-selective cancer treatment based on the use of boron-containing drugs and neutron irradiation. Selective tumor targeting by boron with minimal normal tissue toxicity is required for effective BNCT. Boronophenylalanine (BPA) is widely used as a boron drug for BNCT. In our previous study, we demonstrated that application of the CSF administration method results in high BPA accumulation in the brain tumor even with a low dose of BPA. In this study, we evaluate BPA biodistribution in the brain following application of the CSF method in brain-tumor-model rats (melanoma) utilizing matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). We observed increased BPA penetration to the tumor tissue, where the color contrast on mass images indicates the border of BPA accumulation between tumor and normal cells. Our approach could be useful as drug delivery to different types of brain tumor, including brain metastases of melanoma. Full article

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4 pages, 190 KiB

Open AccessEditorial

Tumor Progression, Microenvironments, and Therapeutics

by Hung-Chi Cheng and Li-Tzu Huang

Life 2022, 12(10), 1599; https://doi.org/10.3390/life12101599 - 14 Oct 2022

Cited by 3 | Viewed by 1150

Abstract

Tumor malignancy starts from transformation [...] Full article

15 pages, 4431 KiB

Open AccessArticle

Alpha-Mangostin Reduces Pericellular Fibronectin on Suspended Tumor Cells and Therapeutically, but Not Prophylactically, Suppresses Distant Metastasis

by Li-Tzu Huang, Chin-Ho Kuo, Lin Tseng, Yi-Syuan Li, Li-Hsin Cheng, Chin-Yun Cheng, Shane-Rong Sheu, Wen-Tsan Chang, Chien-Chin Chen and Hung-Chi Cheng

Life 2022, 12(9), 1375; https://doi.org/10.3390/life12091375 - 2 Sep 2022

Cited by 2 | Viewed by 2699

Abstract

Major cancer deaths can be ascribed to distant metastasis to which the assembly of pericellular fibronectin (periFN) on suspended tumor cells (STCs) in the bloodstream that facilitate endothelial attachment can lead. Even though mangosteen pericarps (MP) extracts and the major component α-mangostin (α-MG) [...] Read more.

Major cancer deaths can be ascribed to distant metastasis to which the assembly of pericellular fibronectin (periFN) on suspended tumor cells (STCs) in the bloodstream that facilitate endothelial attachment can lead. Even though mangosteen pericarps (MP) extracts and the major component α-mangostin (α-MG) exhibit potent cancer chemopreventive properties, whether they can prophylactically and therapeutically be used as dietary nutraceuticals to prevent distant metastasis by suppressing periFN assembly on STCs within the circulation remains obscure. Immunofluorescence staining, MTT assays, flow cytometric assays, immunoblotting, and experimental metastasis mouse models were used to detect the effects of MP extracts or α-MG on periFN on STCs, tumor cell proliferation and apoptosis, the AKT activity, and tumor lung metastasis. The periFN assembly on STCs was significantly diminished upon treatments of STCs with either α-MG or MP extracts in a dose-dependent manner without inhibiting cell proliferation and viability due to increased AKT activity. Pretreatment of STCs with α-MG appeared to suppress tumor lung metastasis and prolong mouse survival rates. Oral gavage with MP extracts could therapeutically, but not prophylactically, prevent lung metastasis of STCs. We concluded that MP extracts or the major component α-MG may therapeutically serve as a potent anti-metastatic nutraceutical. Full article

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7 pages, 1579 KiB

Open AccessCase Report

Thyroid Carcinoma Showing Thymus-like Differentiation (CASTLE): A Case Report

by Mihaela Stanciu, Ruxandra Paula Ristea, Mihaela Popescu, Corina Maria Vasile and Florina Ligia Popa

Life 2022, 12(9), 1314; https://doi.org/10.3390/life12091314 - 26 Aug 2022

Cited by 11 | Viewed by 2402

Abstract

Background and Objectives: Carcinoma showing thymus-like differentiation (CASTLE) is a low-grade thyroid carcinoma, with an indolent clinical course and usually a favorable prognosis. The clinical and imagistic features are not specific for CASTLE but similar to other malignant lesions of the thyroid. Definite [...] Read more.

Background and Objectives: Carcinoma showing thymus-like differentiation (CASTLE) is a low-grade thyroid carcinoma, with an indolent clinical course and usually a favorable prognosis. The clinical and imagistic features are not specific for CASTLE but similar to other malignant lesions of the thyroid. Definite diagnosis is based on an immunohistochemical examination, as this carcinoma shows positive CD5 immunoreactivity when compared to other aggressive thyroid carcinomas. Case presentation: The main focus of this study is to outline a rare case of CASTLE compressing the trachea in a 50-year-old female patient who was initially diagnosed with undifferentiated thyroid carcinoma, for which she underwent unsuccessful surgery, as well as postoperative radiotherapy and chemotherapy. After receiving a second medical opinion, the patient underwent a challenging radical resection consisting in total thyroidectomy and central neck dissection, with no local recurrence after 6 months and 2 years of follow-up and negative metastatic follow-up. The correct diagnosis has been established based on pathological and immunohistochemical examinations. Conclusions: In summary, the diagnosis of CASTLE is difficult and requires an experienced histological analysis and CD5 immunoreactivity. Lack of metastasis, complete removal of the tumor, and a low degree of tumor infiltration into nearby structures are all associated with better long-term survival. Full article

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22 pages, 1052 KiB

Open AccessEditor’s ChoiceReview

Cancer Cachexia and Antitumor Immunity: Common Mediators and Potential Targets for New Therapies

by Konstantinos Rounis, Dimitrios Makrakis, Ioannis Gioulbasanis, Simon Ekman, Luigi De Petris, Dimitris Mavroudis and Sofia Agelaki

Life 2022, 12(6), 880; https://doi.org/10.3390/life12060880 - 12 Jun 2022

Cited by 5 | Viewed by 3004

Abstract

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host’s innate and adaptive immunity. [...] Read more.

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host’s innate and adaptive immunity. Over the last few years, the development of immune checkpoint inhibitors (ICIs) transformed the treatment landscape for a wide spectrum of malignancies, creating an unprecedented opportunity for long term remissions in a significant subset of patients. Early clinical data indicate that CCS adversely impairs treatment outcomes of patients receiving ICIs. We herein reviewed existing evidence on the potential links between the mechanisms that promote the catabolic state in CCS and those that impair the antitumor immune response. We show that the biological mediators and processes leading to the development of CCS may also participate in the modulation and the sustainment of an immune suppressive tumor microenvironment and impaired anti-tumor immunity. Moreover, we demonstrate that the deregulation of the host’s metabolic homeostasis in cancer cachexia is associated with resistance to ICIs. Further research on the interrelation between cancer cachexia and anti-tumor immunity is required for the effective management of resistance to immunotherapy in this specific but large subgroup of ICI treated individuals. Full article

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14 pages, 824 KiB

Open AccessReview

An Insight into the Novel Immunotherapy and Targeted Therapeutic Strategies for Hepatocellular Carcinoma and Cholangiocarcinoma

by Eleni-Myrto Trifylli, Evangelos Koustas, Nikolaos Papadopoulos, Panagiotis Sarantis, Georgios Aloizos, Christos Damaskos, Nikolaos Garmpis, Anna Garmpi and Michalis V. Karamouzis

Life 2022, 12(5), 665; https://doi.org/10.3390/life12050665 - 30 Apr 2022

Cited by 14 | Viewed by 4470

Abstract

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) constitute highly malignant forms of primary liver cancers. Hepatocellular and bile duct carcinogenesis is a multiplex process, caused by various genetic and epigenetic alterations, the influence of environmental factors, as well as the implication of the gut [...] Read more.

Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) constitute highly malignant forms of primary liver cancers. Hepatocellular and bile duct carcinogenesis is a multiplex process, caused by various genetic and epigenetic alterations, the influence of environmental factors, as well as the implication of the gut microbiome, which was undervalued in the previous years. The molecular and immunological analysis of the above malignancies, as well as the identification of the crucial role of intestinal microbiota for hepatic and biliary pathogenesis, opened the horizon for novel therapeutic strategies, such as immunotherapy, and enhanced the overall survival of cancer patients. Some of the immunotherapy strategies that are either clinically applied or under pre-clinical studies include monoclonal antibodies, immune checkpoint blockade, cancer vaccines, as well as the utilization of oncolytic viral vectors and Chimeric antigen, receptor-engineered T (CAR-T) cell therapy. In this current review, we will shed light on the recent therapeutic modalities for the above primary liver cancers, as well as on the methods for the enhancement and optimization of anti-tumor immunity. Full article

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11 pages, 275 KiB

Open AccessEditor’s ChoiceReview

Alcohol Consumption, ALDH2 Polymorphism as Risk Factors for Upper Aerodigestive Tract Cancer Progression and Prognosis

by Che-Hong Chen, Wen-Lun Wang, Ming-Hung Hsu and Daria Mochly-Rosen

Life 2022, 12(3), 348; https://doi.org/10.3390/life12030348 - 27 Feb 2022

Cited by 12 | Viewed by 4273

Abstract

The upper aerodigestive tract (UADT) is highly susceptible to multiple primary cancers originated from squamous epithelia and constitutes a field of cancerization. Patients with head and neck cancer (head and neck squamous cell carcinoma, HNSCC) are at high risk of developing multiple cancers [...] Read more.

The upper aerodigestive tract (UADT) is highly susceptible to multiple primary cancers originated from squamous epithelia and constitutes a field of cancerization. Patients with head and neck cancer (head and neck squamous cell carcinoma, HNSCC) are at high risk of developing multiple cancers in the esophagus (esophageal squamous cell carcinoma, ESCC). Conversely, esophageal cancer patients are prone to develop multiple primary tumors in the head and neck region. The East Asian-specific dysfunctional ALDH2*2 missense mutation is a genetic risk factor for UADT cancer. It is not only associated with increased incidences of UADT cancer, but is also implicated in faster cancer progression and poorer prognosis. Alcohol use is a major lifestyle risk factor which causes UADT cancer among ALDH2*2 carriers. The accumulation of the immediate metabolite of alcohol, acetaldehyde, is likely the genotoxic agents that is involved in the process of tumorigenesis. This review summarizes recent publications on the risk and association of ALDH2*2 mutation, alcohol consumption in synchronous, metachronous UADT cancer. Possible molecular mechanisms involved in cancer initiation, progress and prognosis are discussed. The review also highlights a need for precision medicine-based preventive and therapeutic strategies by integrating lifestyle and genetic risk factors, such as alcohol consumption, genotypes of the alcohol metabolizing genes, ADH1B and ALDH2, into a risk assessment model for better screening, surveillance and treatment outcome. Full article

2021

Jump to: 2022

18 pages, 3415 KiB

Open AccessArticle

Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis

by Funmilayo O. Adeshakin, Adeleye O. Adeshakin, Zhao Liu, Jian Cheng, Pengchao Zhang, Dehong Yan, Guizhong Zhang and Xiaochun Wan

Life 2022, 12(1), 42; https://doi.org/10.3390/life12010042 - 28 Dec 2021

Cited by 8 | Viewed by 3266

Abstract

Metastasis arises owing to tumor cells’ capacity to evade pro-apoptotic signals. Anoikis—the apoptosis of detached cells (from the extracellular matrix (ECM)) is often circumvented by metastatic cells as a result of biochemical and molecular transformations. These facilitate cells’ ability to survive, invade and [...] Read more.

Metastasis arises owing to tumor cells’ capacity to evade pro-apoptotic signals. Anoikis—the apoptosis of detached cells (from the extracellular matrix (ECM)) is often circumvented by metastatic cells as a result of biochemical and molecular transformations. These facilitate cells’ ability to survive, invade and reattach to secondary sites. Here, we identified deregulated glucose metabolism, oxidative phosphorylation, and proteasome in anchorage-independent cells compared to adherent cells. Metformin an anti-diabetic drug that reduces blood glucose (also known to inhibit mitochondrial Complex I), and proteasome inhibitors were employed to target these changes. Metformin or proteasome inhibitors alone increased misfolded protein accumulation, sensitized tumor cells to anoikis, and impaired pulmonary metastasis in the B16F10 melanoma model. Mechanistically, metformin reduced cellular ATP production, activated AMPK to foster pro-apoptotic unfolded protein response (UPR) through enhanced expression of CHOP in ECM detached cells. Furthermore, AMPK inhibition reduced misfolded protein accumulation, thus highlight relevance of AMPK activation in facilitating metformin-induced stress and UPR cell death. Our findings provide insights into the molecular biology of anoikis resistance and identified metformin and proteasome inhibitors as potential therapeutic options for tumor metastasis. Full article

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14 pages, 6918 KiB

Open AccessArticle

The Anti-Proliferative Activity of Secondary Metabolite from the Marine Streptomyces sp. against Prostate Cancer Cells

by Hung-Yu Lin, Yong-Shiou Lin, Shou-Ping Shih, Sung-Bau Lee, Mohamed El-Shazly, Ken-Ming Chang, Yu-Chen S. H. Yang, Yi-Lun Lee and Mei-Chin Lu

Life 2021, 11(12), 1414; https://doi.org/10.3390/life11121414 - 16 Dec 2021

Cited by 12 | Viewed by 3366

Abstract

Many active substances from marine organisms are produced by symbiotic microorganisms such as bacteria, fungi, and algae. Secondary metabolites from marine actinomycetes exhibited several biological activities and provided interesting drug leads. This study reported the isolation of Lu01-M, a secondary metabolite from the [...] Read more.

Many active substances from marine organisms are produced by symbiotic microorganisms such as bacteria, fungi, and algae. Secondary metabolites from marine actinomycetes exhibited several biological activities and provided interesting drug leads. This study reported the isolation of Lu01-M, a secondary metabolite from the marine actinomycetes Streptomyces sp., with potent anti-proliferative activity against prostate cancers. Lu01-M blocked cell proliferation with IC₅₀ values of 1.03 ± 0.31, 2.12 ± 0.38, 1.27 ± 0.25 μg/mL in human prostate cancer PC3, DU145, and LNCaP cells, respectively. Lu01-M induced cytotoxic activity through multiple mechanisms including cell apoptosis, necroptosis, autophagy, ER stress, and inhibiting colony formation and cell migration. Lu01-M induced cell cycle arrest at the G2/M phase and DNA damage. However, the activity of autophagy induced survival response in cancer cells. Our findings suggested that Lu01-M holds the potential to be developed as an anti-cancer agent against prostate cancers. Full article

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17 pages, 5027 KiB

Open AccessArticle

Anticancer Effects of Midazolam on Lung and Breast Cancers by Inhibiting Cell Proliferation and Epithelial-Mesenchymal Transition

by Hsin-Ling Lu, King-Chuen Wu, Char-Wen Chen, Hung-Kai Weng, Bu-Miin Huang, Ting-Yu Lin, Ming-Hsin Liu, Edmund-Cheung So, Ruey-Mo Lin and Yang-Kao Wang

Life 2021, 11(12), 1396; https://doi.org/10.3390/life11121396 - 13 Dec 2021

Cited by 9 | Viewed by 3081

Abstract

Despite improvements in cancer treatments resulting in higher survival rates, the proliferation and metastasis of tumors still raise new questions in cancer therapy. Therefore, new drugs and strategies are still needed. Midazolam (MDZ) is a common sedative drug acting through the γ-aminobutyric acid [...] Read more.

Despite improvements in cancer treatments resulting in higher survival rates, the proliferation and metastasis of tumors still raise new questions in cancer therapy. Therefore, new drugs and strategies are still needed. Midazolam (MDZ) is a common sedative drug acting through the γ-aminobutyric acid receptor in the central nervous system and also binds to the peripheral benzodiazepine receptor (PBR) in peripheral tissues. Previous studies have shown that MDZ inhibits cancer cell proliferation but increases cancer cell apoptosis through different mechanisms. In this study, we investigated the possible anticancer mechanisms of MDZ on different cancer cell types. MDZ inhibited transforming growth factor β (TGF-β)-induced cancer cell proliferation of both A549 and MCF-7 cells. MDZ also inhibited TGF-β-induced cell migration, invasion, epithelial-mesenchymal-transition, and Smad phosphorylation in both cancer cell lines. Inhibition of PBR by PK11195 rescued the MDZ-inhibited cell proliferation, suggesting that MDZ worked through PBR to inhibit TGF-β pathway. Furthermore, MDZ inhibited proliferation, migration, invasion and levels of mesenchymal proteins in MDA-MD-231 triple-negative breast cancer cells. Together, MDZ inhibits cancer cell proliferation both in epithelial and mesenchymal types and EMT, indicating an important role for MDZ as a candidate to treat lung and breast cancers. Full article

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15 pages, 2045 KiB

Open AccessArticle

Double Recombinant Vaccinia Virus: A Candidate Drug against Human Glioblastoma

by Natalia Vasileva, Alisa Ageenko, Maria Dmitrieva, Anna Nushtaeva, Sergey Mishinov, Galina Kochneva, Vladimir Richter and Elena Kuligina

Life 2021, 11(10), 1084; https://doi.org/10.3390/life11101084 - 14 Oct 2021

Cited by 17 | Viewed by 2801

Abstract

Glioblastoma is one of the most aggressive brain tumors. Given the poor prognosis of this disease, novel methods for glioblastoma treatment are needed. Virotherapy is one of the most actively developed approaches for cancer therapy today. VV-GMCSF-Lact is a recombinant vaccinia virus with [...] Read more.

Glioblastoma is one of the most aggressive brain tumors. Given the poor prognosis of this disease, novel methods for glioblastoma treatment are needed. Virotherapy is one of the most actively developed approaches for cancer therapy today. VV-GMCSF-Lact is a recombinant vaccinia virus with deletions of the viral thymidine kinase and growth factor genes and insertions of the granulocyte–macrophage colony-stimulating factor and oncotoxic protein lactaptin genes. The virus has high cytotoxic activity against human cancer cells of various histogenesis and antitumor efficacy against breast cancer. In this work, we show VV-GMCSF-Lact to be a promising therapeutic agent for glioblastoma treatment. VV-GMCSF-Lact effectively decreases the viability of glioblastoma cells of both immortalized and patient-derived cultures in vitro, crosses the blood–brain barrier, selectively replicates into orthotopically transplanted human glioblastoma when intravenously injected, and inhibits glioblastoma xenograft and metastasis growth when injected intratumorally. Full article

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22 pages, 5041 KiB

Open AccessEditor’s ChoiceReview

Roles and Mechanisms of Deubiquitinases (DUBs) in Breast Cancer Progression and Targeted Drug Discovery

by Sixuan Li, Hongquan Zhang and Xiaofan Wei

Life 2021, 11(9), 965; https://doi.org/10.3390/life11090965 - 14 Sep 2021

Cited by 10 | Viewed by 3879

Abstract

Deubiquitinase (DUB) is an essential component in the ubiquitin—proteasome system (UPS) by removing ubiquitin chains from substrates, thus modulating the expression, activity, and localization of many proteins that contribute to tumor development and progression. DUBs have emerged as promising prognostic indicators and drug [...] Read more.

Deubiquitinase (DUB) is an essential component in the ubiquitin—proteasome system (UPS) by removing ubiquitin chains from substrates, thus modulating the expression, activity, and localization of many proteins that contribute to tumor development and progression. DUBs have emerged as promising prognostic indicators and drug targets. DUBs have shown significant roles in regulating breast cancer growth, metastasis, resistance to current therapies, and several canonical oncogenic signaling pathways. In addition, specific DUB inhibitors have been identified and are expected to benefit breast cancer patients in the future. Here, we review current knowledge about the effects and molecular mechanisms of DUBs in breast cancer, providing novel insight into treatments of breast cancer-targeting DUBs. Full article

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12 pages, 1919 KiB

Open AccessArticle

Calcitriol Suppresses Warburg Effect and Cell Growth in Human Colorectal Cancer Cells

by Chun-Yin Huang, Yu-Ting Weng, Po-Chen Li, Nien-Tsu Hsieh, Chun-I Li, Hsiao-Sheng Liu and Ming-Fen Lee

Life 2021, 11(9), 963; https://doi.org/10.3390/life11090963 - 14 Sep 2021

Cited by 20 | Viewed by 2755

Abstract

Increasing lines of evidence indicate that the biologically active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D₃), prevents cancer progression by reducing cell proliferation, increasing cell differentiation, and inhibiting angiogenesis, among other potential roles. Cancer cells in solid tumors preferably undergo the [...] Read more.

Increasing lines of evidence indicate that the biologically active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D₃), prevents cancer progression by reducing cell proliferation, increasing cell differentiation, and inhibiting angiogenesis, among other potential roles. Cancer cells in solid tumors preferably undergo the “Warburg effect” to support cell growth by upregulating glycolysis, and the glycolytic intermediates further serve as building blocks to generate biomass. The objective of the current study is to investigate whether calcitriol affects glucose metabolism and cell growth in human colorectal cancer cells. Calcitriol reduced the expression of cyclin D1 and c-Myc. In addition, calcitriol reduced the expression of glucose transporter 1 (GLUT1) and key glycolytic enzymes and decreased extracellular acidification rate but increased oxygen consumption rate in human colorectal cancer cells. In a subcutaneous HT29 xenograft NOD/SCID mouse model, the volume and weight of the tumors were smaller in the calcitriol groups as compared with the control group, and the expression levels of GLUT1 and glycolytic enzymes, hexokinase 2 and lactate dehydrogenase A, were also lower in the calcitriol groups in a dose-responsive manner. Our data indicate that calcitriol suppresses glycolysis and cell growth in human colorectal cancer cells, suggesting an inhibitory role of the biologically active form of vitamin D in colorectal cancer progression. Full article

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16 pages, 4453 KiB

Open AccessArticle

Arginine Methyltransferase PRMT1 Regulates p53 Activity in Breast Cancer

by Li-Ming Liu, Qiang Tang, Xin Hu, Jing-Jing Zhao, Yuan Zhang, Guo-Guang Ying and Fei Zhang

Life 2021, 11(8), 789; https://doi.org/10.3390/life11080789 - 5 Aug 2021

Cited by 16 | Viewed by 3100

Abstract

The protein p53 is one of the most important tumor suppressors, responding to a variety of stress signals. Mutations in p53 occur in about half of human cancer cases, and dysregulation of the p53 function by epigenetic modifiers and modifications is prevalent in [...] Read more.

The protein p53 is one of the most important tumor suppressors, responding to a variety of stress signals. Mutations in p53 occur in about half of human cancer cases, and dysregulation of the p53 function by epigenetic modifiers and modifications is prevalent in a large proportion of the remainder. PRMT1 is the main enzyme responsible for the generation of asymmetric-dimethylarginine, whose upregulation or aberrant splicing has been observed in many types of malignancies. Here, we demonstrate that p53 function is regulated by PRMT1 in breast cancer cells. PRMT1 knockdown activated the p53 signal pathway and induced cell growth-arrest and senescence. PRMT1 could directly bind to p53 and inhibit the transcriptional activity of p53 in an enzymatically dependent manner, resulting in a decrease in the expression levels of several key downstream targets of the p53 pathway. We were able to detect p53 asymmetric-dimethylarginine signals in breast cancer cells and breast cancer tissues from patients, and the signals could be significantly weakened by silencing of PRMT1 with shRNA, or inhibiting PRMT1 activity with a specific inhibitor. Furthermore, PRMT1 inhibitors significantly impeded cell growth and promoted cellular senescence in breast cancer cells and primary tumor cells. These results indicate an important role of PRMT1 in the regulation of p53 function in breast tumorigenesis. Full article

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19 pages, 1540 KiB

Open AccessReview

Current Knowledge of Long Non-Coding RNA HOTAIR in Breast Cancer Progression and Its Application

by Yubo Shi, Qingyun Huang, Xinyu Kong, Ruichen Zhao, Xinyue Chen, Yujia Zhai and Lixia Xiong

Life 2021, 11(6), 483; https://doi.org/10.3390/life11060483 - 26 May 2021

Cited by 10 | Viewed by 4122

Abstract

Breast cancer is one of the most devastating cancers with high morbidity and mortality in females worldwide. Breast tumorigenesis and further development present great uncertainty and complexity, and efficient therapeutic approaches still lack. Accumulating evidence indicates HOX transcript antisense intergenic RNA (HOTAIR) is [...] Read more.

Breast cancer is one of the most devastating cancers with high morbidity and mortality in females worldwide. Breast tumorigenesis and further development present great uncertainty and complexity, and efficient therapeutic approaches still lack. Accumulating evidence indicates HOX transcript antisense intergenic RNA (HOTAIR) is dysregulated in cancers and has emerged as a novel hotspot in the field. In breast cancer, aberrant HOTAIR expression is responsible for advanced tumor progression by regulating multifarious signaling pathways. Besides, HOTAIR may act as competitive endogenous RNA to bind to several microRNAs and suppress their expressions, which can subsequently upregulate the levels of targeted downstream messenger RNAs, thereby leading to further cancer progression. In addition, HOTAIR works as a promising biomarker and predictor for breast cancer patients’ diagnosis or outcome prediction. Recently, HOTAIR is potentially considered to be a drug target. Here, we have summarized the induction of HOTAIR in breast cancer and its impacts on cell proliferation, migration, apoptosis, and therapeutic resistance, as well as elucidating the underlying mechanisms. This review aims to provide new insights into investigations between HOTAIR and breast cancer development and inspire new methods for studying the association in depth. Full article

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18 pages, 4119 KiB

Open AccessArticle

Ionizing Radiation Induces Resistant Glioblastoma Stem-Like Cells by Promoting Autophagy via the Wnt/β-Catenin Pathway

by Cheng-Yu Tsai, Huey-Jiun Ko, Chi-Ying F. Huang, Ching-Yi Lin, Shean-Jaw Chiou, Yu-Feng Su, Ann-Shung Lieu, Joon-Khim Loh, Aij-Lie Kwan, Tsung-Hsien Chuang and Yi-Ren Hong

Life 2021, 11(5), 451; https://doi.org/10.3390/life11050451 - 18 May 2021

Cited by 12 | Viewed by 3351

Abstract

Therapeutic resistance in recurrent glioblastoma multiforme (GBM) after concurrent chemoradiotherapy (CCRT) is a challenging issue. Although standard fractionated radiation is essential to treat GBM, it has led to local recurrence along with therapy-resistant cells in the ionizing radiation (IR) field. Lines of evidence [...] Read more.

Therapeutic resistance in recurrent glioblastoma multiforme (GBM) after concurrent chemoradiotherapy (CCRT) is a challenging issue. Although standard fractionated radiation is essential to treat GBM, it has led to local recurrence along with therapy-resistant cells in the ionizing radiation (IR) field. Lines of evidence showed cancer stem cells (CSCs) play a vital role in therapy resistance in many cancer types, including GBM. However, the molecular mechanism is poorly understood. Here, we proposed that autophagy could be involved in GSC induction for radioresistance. In a clinical setting, patients who received radiation/chemotherapy had higher LC3II expression and showed poor overall survival compared with those with low LC3 II. In a cell model, U87MG and GBM8401 expressed high level of stemness markers CD133, CD44, Nestin, and autophagy marker P62/LC3II after receiving standard fractionated IR. Furthermore, Wnt/β-catenin proved to be a potential pathway and related to P62 by using proteasome inhibitor (MG132). Moreover, pharmacological inhibition of autophagy with BAF and CQ inhibit GSC cell growth by impairing autophagy flux as demonstrated by decrease Nestin, CD133, and SOX-2 levels. In conclusion, we demonstrated that fractionated IR could induce GSCs with the stemness phenotype by P62-mediated autophagy through the Wnt/β-catenin for radioresistance. This study offers a new therapeutic strategy for targeting GBM in the future. Full article

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