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Liu B, Liu L, Liu Y. Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy. Front Immunol 2024; 15:1450487. [PMID: 39315094 PMCID: PMC11416969 DOI: 10.3389/fimmu.2024.1450487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 08/21/2024] [Indexed: 09/25/2024] Open
Abstract
Ferroptosis is a type of cell death that plays a remarkable role in the growth and advancement of malignancies including hepatocellular carcinoma (HCC). Non-coding RNAs (ncRNAs) have a considerable impact on HCC by functioning as either oncogenes or suppressors. Recent research has demonstrated that non-coding RNAs (ncRNAs) have the ability to control ferroptosis in HCC cells, hence impacting the advancement of tumors and the resistance of these cells to drugs. Autophagy is a mechanism that is conserved throughout evolution and plays a role in maintaining balance in the body under normal settings. Nevertheless, the occurrence of dysregulation of autophagy is evident in the progression of various human disorders, specifically cancer. Autophagy plays dual roles in cancer, potentially influencing both cell survival and cell death. HCC is a prevalent kind of liver cancer, and genetic mutations and changes in molecular pathways might worsen its advancement. The role of autophagy in HCC is a subject of debate, as it has the capacity to both repress and promote tumor growth. Autophagy activation can impact apoptosis, control proliferation and glucose metabolism, and facilitate tumor spread through EMT. Inhibiting autophagy can hinder the growth and spread of HCC and enhance the ability of tumor cells to respond to treatment. Autophagy in HCC is regulated by several signaling pathways, such as STAT3, Wnt, miRNAs, lncRNAs, and circRNAs. Utilizing anticancer drugs to target autophagy may have advantageous implications for the efficacy of cancer treatment.
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Affiliation(s)
- Beibei Liu
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ling Liu
- Division of Biliary Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Liu
- Day Surgery Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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High-throughput screening for natural compound-based autophagy modulators reveals novel chemotherapeutic mode of action for arzanol. Cell Death Dis 2021; 12:560. [PMID: 34059630 PMCID: PMC8167120 DOI: 10.1038/s41419-021-03830-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 12/17/2022]
Abstract
Autophagy is an intracellular recycling pathway with implications for intracellular homeostasis and cell survival. Its pharmacological modulation can aid chemotherapy by sensitizing cancer cells toward approved drugs and overcoming chemoresistance. Recent translational data on autophagy modulators show promising results in reducing tumor growth and metastasis, but also reveal a need for more specific compounds and novel lead structures. Here, we searched for such autophagy-modulating compounds in a flow cytometry-based high-throughput screening of an in-house natural compound library. We successfully identified novel inducers and inhibitors of the autophagic pathway. Among these, we identified arzanol as an autophagy-modulating drug that causes the accumulation of ATG16L1-positive structures, while it also induces the accumulation of lipidated LC3. Surprisingly, we observed a reduction of the size of autophagosomes compared to the bafilomycin control and a pronounced accumulation of p62/SQSTM1 in response to arzanol treatment in HeLa cells. We, therefore, speculate that arzanol acts both as an inducer of early autophagosome biogenesis and as an inhibitor of later autophagy events. We further show that arzanol is able to sensitize RT-112 bladder cancer cells towards cisplatin (CDDP). Its anticancer activity was confirmed in monotherapy against both CDDP-sensitive and -resistant bladder cancer cells. We classified arzanol as a novel mitotoxin that induces the fragmentation of mitochondria, and we identified a series of targets for arzanol that involve proteins of the class of mitochondria-associated quinone-binding oxidoreductases. Collectively, our results suggest arzanol as a valuable tool for autophagy research and as a lead compound for drug development in cancer therapy.
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Chen C, Chen S, Hu X, Wang J, Wen T, Fu J, Li H. Effects of autophagy-associated genes on the prognosis for lung adenocarcinoma. Transl Cancer Res 2020; 9:1947-1959. [PMID: 35117541 PMCID: PMC8798140 DOI: 10.21037/tcr.2020.02.07] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 02/04/2020] [Indexed: 12/29/2022]
Abstract
Background Several studies show that autophagy plays an important part in the biological processes of lung adenocarcinoma. Therefore, this work aimed to establish one scoring system on the basis of the expression profiles of differentially expressed autophagy-related genes (DEARGs) in patients with lung adenocarcinoma. Methods The Cancer Genome Atlas (TCGA) was applied to retrieve lung adenocarcinoma data. The overall survival (OS)-associated DEARGs were selected for the DEARG scoring scale. Moreover, the online database Kaplan-Meier Plotter (www.Kmplot.com) was employed to verify the accuracy of our results. Results The expression patterns of DEARG were detected in lung adenocarcinoma as well as normal lung tissues. A gene set related to autophagy was identified, along with 9 genes that showed marked significance in predicting the lung adenocarcinoma prognosis. According to the cox regression results, DEARGs (including ITGB4, BIRC5, ERO1A, and NLRC4) were applied to calculate the DEARGs risk score. Patients with lower DEARGs risk scores were associated with better OS. Moreover, based on analysis with the receiver operating characteristic (ROC) curve, DEARGs accurately distinguished the healthy tissues from lung adenocarcinoma tissues [area under the curve (AUC) value of >0.6]. Conclusions A scoring system is constructed based on the primary DEARGs, which accurately predicts the outcomes of lung adenocarcinoma.
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Affiliation(s)
- Chongxiang Chen
- Department of Intensive Care Unit, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.,Guangzhou Institute of Respiratory Diseases, State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China
| | - Siliang Chen
- Department of Hematology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Xiaochun Hu
- Department of Hematology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Jiaojiao Wang
- Department of Tuberculosis, Fuzhou Pulmonary Hospital of Fujian, Teaching Hospital of Fujian Medical University, Fuzhou 350008, China
| | - Tianmeng Wen
- School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Juan Fu
- Department of Ultrasound and Electrocardiogram, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Huan Li
- Department of Intensive Care Unit, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
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Wei R, Xiao Y, Song Y, Yuan H, Luo J, Xu W. FAT4 regulates the EMT and autophagy in colorectal cancer cells in part via the PI3K-AKT signaling axis. J Exp Clin Cancer Res 2019; 38:112. [PMID: 30832706 PMCID: PMC6399964 DOI: 10.1186/s13046-019-1043-0] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 01/15/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND FAT4 functions as a tumor suppressor, and previous findings have demonstrated that FAT4 can inhibit the epithelial-to-mesenchymal transition (EMT) and the proliferation of gastric cancer cells. However, few studies have investigated the role of FAT4 in the development of colorectal cancer (CRC). The current study aimed to detect the role of FAT4 in the invasion, migration, proliferation and autophagy of CRC and elucidate the probable molecular mechanisms through which FAT4 interacts with these processes. METHODS Transwell invasion assays, MTT assays, transmission electron microscopy, immunohistochemistry and western blotting were performed to evaluate the migration, invasion, proliferation and autophagy abilities of CRC cells, and the levels of active molecules involved in PI3K/AKT signaling were examined through a western blotting analysis. In addition, the function of FAT4 in vivo was assessed using a tumor xenograft model. RESULTS FAT4 expression in CRC tissues was weaker than that in nonmalignant tissues and could inhibit cell invasion, migration, and proliferation by promoting autophagy in vitro. Furthermore, the regulatory effects of FAT4 on autophagy and the EMT were partially attributed to the PI3K-AKT signaling pathway. The results in vivo also showed that FAT4 modulated CRC tumorigenesis. CONCLUSION FAT4 can regulate the activity of PI3K to promote autophagy and inhibit the EMT in part through the PI3K/AKT/mTOR and PI3K/AKT/GSK-3β signaling pathways.
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Affiliation(s)
- Ran Wei
- The First Clinical Medical College, Nanchang University, Nanchang, 330006 Jiangxi China
| | - Yuhong Xiao
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi China
| | - Yi Song
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi China
| | - Huiping Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi China
| | - Jun Luo
- Department of Rehabilitation Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi China
| | - Wei Xu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006 Jiangxi China
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Huang F, Wang BR, Wang YG. Role of autophagy in tumorigenesis, metastasis, targeted therapy and drug resistance of hepatocellular carcinoma. World J Gastroenterol 2018; 24:4643-4651. [PMID: 30416312 PMCID: PMC6224467 DOI: 10.3748/wjg.v24.i41.4643] [Citation(s) in RCA: 141] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/04/2018] [Accepted: 10/05/2018] [Indexed: 02/06/2023] Open
Abstract
Autophagy is a “self-degradative” process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.
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Affiliation(s)
- Fang Huang
- Department of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Bing-Rong Wang
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
| | - Yi-Gang Wang
- Department of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
- Xinyuan Institute of Medicine and Biotechnology, School of Life Sciences, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China
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Delou JMA, Biasoli D, Borges HL. The Complex Link between Apoptosis and Autophagy: a Promising New Role for RB. AN ACAD BRAS CIENC 2018; 88:2257-2275. [PMID: 27991962 DOI: 10.1590/0001-3765201620160127] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2016] [Accepted: 06/27/2016] [Indexed: 12/14/2022] Open
Abstract
Physiological processes, as autophagy, proliferation and apoptosis are affected during carcinogenesis. Restoring cellular sensitivity to apoptotic stimuli, such as the antineoplastic cocktails, has been explored as a strategy to eliminate cancer cells. Autophagy, a physiological process of recycling organelles and macromolecules can be deviated from homeostasis to support cancer cells survival, proliferation, escape from apoptosis, and therapy resistance. The relationship between autophagy and apoptosis is complex and many stimuli can induce both processes. Most chemotherapeutic agents induce autophagy and it is not clear whether and how this chemotherapy-induced autophagy might contribute to resistance to apoptosis. Here, we review current strategies to sensitize cancer cells by interfering with autophagy. Moreover, we discuss a new link between autophagy and apoptosis: the tumor suppressor retinoblastoma protein (RB). Inactivation of RB is one of the earliest and more frequent hallmarks of cancer transformation, known to control cell cycle progression and apoptosis. Therefore, understanding RB functions in controlling cell fate is essential for an effective translation of RB status in cancer samples to the clinical outcome.
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Affiliation(s)
- João M A Delou
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Ilha do Fundão, 21949-590 Rio de Janeiro, RJ, Brazil
| | - Deborah Biasoli
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Ilha do Fundão, 21949-590 Rio de Janeiro, RJ, Brazil
| | - Helena L Borges
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Av. Carlos Chagas Filho, 373, Ilha do Fundão, 21949-590 Rio de Janeiro, RJ, Brazil
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Wang X, Li S, Wu S, Xie L, Wang P. Silence of Beclin1 in oral squamous cell carcinoma cells promotes proliferation, inhibits apoptosis, and enhances chemosensitivity. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:8424-8433. [PMID: 31966694 PMCID: PMC6965406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 07/14/2017] [Indexed: 06/10/2023]
Abstract
Increasing evidence indicates that autophagy plays an important role in regulating proliferation and apoptosis in several human diseases, including cancer. Beclin1 is the first tumor-suppressor gene in mammals involved in the regulation of autophagy. However, the function of Beclin1 in oral cancer cells is not clear at present. We investigated the effects of Beclin1 on the biological characteristics of oral carcinoma cells by Small interfering RNA (siRNA) technology. We found that Beclin1 silencing promoted proliferation, migration, and invasion of oral squamous cell carcinoma cells, and inhibited apoptosis primarily associated with upregulation of survivin and bcl-2. Further, Beclin1 silencing enhanced chemosensitivity to cisplatin. Thus, the Beclin1 gene is expected to become a new therapeutic target for oral cancer.
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Affiliation(s)
- Xia Wang
- Department of Pathology, Binzhou Medical UniversityYantai, Shandong, China
| | - Shu Li
- Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Department of Periodontology, School of Stomatology Shandong UniversityJinan, Shandong, China
| | - Shuhua Wu
- Department of Pathology, Binzhou Medical UniversityYantai, Shandong, China
| | - Lulu Xie
- Medical Imaging Research Institute, Binzhou Medical UniversityYantai, Shandong, China
| | - Peiyuan Wang
- Medical Imaging Research Institute, Binzhou Medical UniversityYantai, Shandong, China
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Wang SF, Wu MY, Cai CZ, Li M, Lu JH. Autophagy modulators from traditional Chinese medicine: Mechanisms and therapeutic potentials for cancer and neurodegenerative diseases. JOURNAL OF ETHNOPHARMACOLOGY 2016; 194:861-876. [PMID: 27793785 DOI: 10.1016/j.jep.2016.10.069] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 10/19/2016] [Accepted: 10/21/2016] [Indexed: 06/06/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine (TCM), an ancient yet still alive medicinal system widely used in East Asia, has played an essential role in health maintenance and diseases control, for a wide range of human chronic diseases like cancers and neurodegenerative diseases. TCM-derived compounds and extracts attract wide attention for their potential application as therapeutic agents against above mentioned diseases. AIM OF REVIEW Recent years the enthusiasm in searching for autophagy regulators for human diseases has yielded many positive hits. TCM-derived compounds as important sources for drug discovery have been widely tested in different models for autophagy modulation. Here we summarize the current progress in the discovery of natural autophagy regulators from TCM for the therapeutic application in cancer and neurodegenerative disease models, aiming to provide the direct link from traditional use to new pharmacological application. METHODS The present review collected the literature published during the recent 10 years which studied the effect of TCM-derived compounds or extracts on autophagy regulation from PubMed, Web of Science, Google Scholar and Science Direct. The names of chemical compounds studied in this article are corresponding to the information in journal plant list. RESULTS In this review, we give a brief introduction about the autophagy and its roles in cancer and neurodegenerative disease models and describe the molecular mechanisms of autophagy modulation. We also make comprehensive lists to summarize the effects and underlying mechanisms of TCM-derived autophagy regulators in cancer and neurodegenerative disease models. In the end of the review, we discuss the current strategies, problems and future direction for TCM-derived autophagy regulators in the treatment of human diseases. CONCLUSIONS A number of data from in vivo and in vitro models indicated TCM derived compounds and extracts hold great potential for the treatment of human diseases including cancers and neurodegenerative diseases. Autophagy, as a novel and promising drug target involved in a wide range of human diseases, can be modulated by many TCM derived agents, indicating autophagy modulation may be an important mechanism underlying the therapeutic effect of TCM in treating diseases. Furthermore, we look forward to seeing the discovery of ideal autophagy modulators from TCM with considerably higher selectivity for the treatment of human diseases.
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Affiliation(s)
- Sheng-Fang Wang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
| | - Ming-Yue Wu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
| | - Cui-Zan Cai
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
| | - Min Li
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong
| | - Jia-Hong Lu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau
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9
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Jain S, Suklabaidya S, Das B, Raghav SK, Batra SK, Senapati S. TLR4 activation by lipopolysaccharide confers survival advantage to growth factor deprived prostate cancer cells. Prostate 2015; 75:1020-33. [PMID: 25833062 DOI: 10.1002/pros.22983] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 01/23/2015] [Indexed: 02/01/2023]
Abstract
BACKGROUND Prostate cancer (PCa) cells express Toll-like receptor-4 (TLR4), a known pro-tumorigenic molecule for different cancer cells. The cancer cells residing in the avascular region of the tumor confront various metabolic stresses and continuously adapt mechanisms to overcome them. We hypothesized that TLR4 activation might provide direct survival advantage to metabolically stressed PCa cells. METHODS We first investigated the effect of LPS on survival of serum deprived PCa cells. To understand the molecular mechanisms involved in TLR4 mediated PCa survival, we next investigated change in expression of markers for apoptosis, senescence and autophagy. Ultimately, the effect of LPS on established prostate tumors was confirmed in vivo using a syngeneic rat model for PCa. RESULTS Lipopolysaccharide (LPS)-mediated TLR4 activation significantly enhanced survival of serum deprived (SD) PC3, DU145 and MAT-LyLu PCa cells. TLR4 inhibition by a specific inhibitor resulted in rapid death of SD-PC3 cells, which was significantly suppressed by LPS. Interestingly, LPS treatment suppressed macroautophagy in SD-PC3 cells and increased expression of CCL2 (C-C motif ligand-2), a known autophagy inhibitor and pro-survival factor. Intra-tumor LPS injection resulted in increased tumor mass, induced TLR4 activation, suppressed autophagy, and increased the macrophage population in MAT-LyLu-tumors. CONCLUSIONS Our study reveals that bacterial LPS enhance survival of PCa cells under conditions of nutrient stress through TLR4 activation. Moreover, LPS induces overexpression of CCL2 involved in the suppression of starvation-induced macroautophagy in PCa cells, and enhanced macrophage population in prostate tumors in vivo. Taken together, the current study suggests the importance of bacterial infection or TLR4-activation in prostate cancer pathogenesis.
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Affiliation(s)
- Sumeet Jain
- Institute of Life Sciences, Bhubaneswar, Odisha, India
- Manipal University, Manipal, Karnataka, India
| | - Sujit Suklabaidya
- Institute of Life Sciences, Bhubaneswar, Odisha, India
- Manipal University, Manipal, Karnataka, India
| | - Biswajit Das
- Institute of Life Sciences, Bhubaneswar, Odisha, India
| | | | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, Buffett Cancer Center, Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, Nebraska
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Wolfson E, Schmukler E, Schokoroy ST, Kloog Y, Pinkas-Kramarski R. Enhancing FTS (Salirasib) efficiency via combinatorial treatment. Biol Cell 2015; 107:130-43. [PMID: 25735913 DOI: 10.1111/boc.201400087] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 02/26/2015] [Indexed: 11/29/2022]
Abstract
The Ras oncogene transmits signals, which regulate various cellular processes including cell motility, differentiation, growth and death. Since Ras signalling is abnormally activated in more than 30% of human cancers, Ras and its downstream signalling pathways are considered good targets for therapeutic interference. Ras is post-translationally modified by the addition of a farnesyl group, which permits its attachment to the plasma membrane. Exploiting this knowledge, a synthetic Ras inhibitor, S-trans, trans-farnesylthiosalicylic acid (FTS; Salirasib), was developed. FTS resembles the farnesylcysteine group of Ras, and acts as an effective Ras antagonist. In the present review, the effect of FTS in combination with various other drugs, as tested in vitro and in vivo, and its therapeutic potential are discussed. As reviewed, FTS cooperates with diverse therapeutic agents, which significantly improves treatment outcome. Therefore, combinations of FTS with other agents have a potential to serve as anti-cancer or anti-inflammatory therapies.
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Affiliation(s)
- Eya Wolfson
- Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel
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Wojton J, Elder J, Kaur B. How efficient are autophagy inhibitors as treatment for glioblastoma? CNS Oncol 2015; 3:5-7. [PMID: 25054892 DOI: 10.2217/cns.13.52] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Jeffrey Wojton
- Dardinger Laboratory for Neuro-oncology & Neurosciences, Department of Neurological Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Ichim G, Lopez J, Ahmed SU, Muthalagu N, Giampazolias E, Delgado ME, Haller M, Riley JS, Mason SM, Athineos D, Parsons MJ, van de Kooij B, Bouchier-Hayes L, Chalmers AJ, Rooswinkel RW, Oberst A, Blyth K, Rehm M, Murphy DJ, Tait SWG. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol Cell 2015; 57:860-872. [PMID: 25702873 PMCID: PMC4352766 DOI: 10.1016/j.molcel.2015.01.018] [Citation(s) in RCA: 348] [Impact Index Per Article: 34.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 10/24/2014] [Accepted: 01/08/2015] [Indexed: 12/25/2022]
Abstract
During apoptosis, the mitochondrial outer membrane is permeabilized, leading to the release of cytochrome c that activates downstream caspases. Mitochondrial outer membrane permeabilization (MOMP) has historically been thought to occur synchronously and completely throughout a cell, leading to rapid caspase activation and apoptosis. Using a new imaging approach, we demonstrate that MOMP is not an all-or-nothing event. Rather, we find that a minority of mitochondria can undergo MOMP in a stress-regulated manner, a phenomenon we term “minority MOMP.” Crucially, minority MOMP leads to limited caspase activation, which is insufficient to trigger cell death. Instead, this caspase activity leads to DNA damage that, in turn, promotes genomic instability, cellular transformation, and tumorigenesis. Our data demonstrate that, in contrast to its well-established tumor suppressor function, apoptosis also has oncogenic potential that is regulated by the extent of MOMP. These findings have important implications for oncogenesis following either physiological or therapeutic engagement of apoptosis.
MOMP can occur in a minority of mitochondria Minority MOMP triggers caspase activity but fails to kill cells Minority MOMP-induced caspase activity causes DNA damage and genomic instability Minority MOMP promotes cellular transformation and tumorigenesis
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Affiliation(s)
- Gabriel Ichim
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Jonathan Lopez
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Shafiq U Ahmed
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Nathiya Muthalagu
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Evangelos Giampazolias
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - M Eugenia Delgado
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland, Baylor College of Medicine, Houston, TX 77030, USA
| | - Martina Haller
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Joel S Riley
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Susan M Mason
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Dimitris Athineos
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Melissa J Parsons
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics-Hematology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Bert van de Kooij
- Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Lisa Bouchier-Hayes
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics-Hematology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Anthony J Chalmers
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Rogier W Rooswinkel
- Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands
| | - Andrew Oberst
- Department of Immunology, University of Washington, 750 Republican Street, Seattle, WA 98109, USA
| | - Karen Blyth
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Markus Rehm
- Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin 2, Ireland, Baylor College of Medicine, Houston, TX 77030, USA
| | - Daniel J Murphy
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
| | - Stephen W G Tait
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
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13
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Yang Z, Ghoorun RA, Fan X, Wu P, Bai Y, Li J, Chen H, Wang L, Wang J. High expression of Beclin-1 predicts favorable prognosis for patients with colorectal cancer. Clin Res Hepatol Gastroenterol 2015; 39:98-106. [PMID: 25130795 DOI: 10.1016/j.clinre.2014.06.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 05/23/2014] [Accepted: 06/12/2014] [Indexed: 02/04/2023]
Abstract
PURPOSE Beclin-1 is an autophagy gene. It promotes the formation of the autophagic vesicle as well as plays an essential role in guarding the cells against chromosomal instability. Overexpression of Beclin-1 has been reported to predict a favorable survival in various cancers. However, little is known about its prognostic significance in colorectal cancer. METHODS AND MATERIALS A total of three hundred and sixty-three (363) colorectal tissues from colorectal cancer (CRC) patients were collected. Tissue micro-arrays and immunohistochemistry were used to investigate the expression and prognostic significance of Beclin-1 in CRC. The associations among Beclin-1 expression, clinicopathological parameters and prognosis were evaluated. RESULTS Beclin-1 had a higher expression in CRC tissues than in normal tissues. A high expression of Beclin-1 was positively correlated with gender (P=0.027), histological grade (P=0.003), pM status (P=0.003) and clinical stage (P=0.024). Patients with a high Beclin-1 expression, when compared to those with a lower expression had both a better overall survival (OS, P=0.006) and disease-free survival (DFS, P=0.008). In the pT3 subgroup, Beclin-1 was also found to be a good prognostic indicator (P<0.05). Multivariate analysis showed a high expression of Beclin-1 was indeed a positive independent prognostic factor of OS and DFS for CRC patients (P<0.05). CONCLUSION Our results demonstrated that a high expression of Beclin-1 correlated with a better overall survival and disease-free survival, thus serving as a favorable independent prognostic marker in CRC.
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Affiliation(s)
- Zuli Yang
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University Guangzhou, Guangzhou, PR China
| | - Roshan Ara Ghoorun
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University Guangzhou, Guangzhou, PR China
| | - Xinjuan Fan
- Gastrointestinal Institute, Sun Yat-Sen University Guangzhou, Guangzhou, PR China
| | - Peihuang Wu
- Gastrointestinal Institute, Sun Yat-Sen University Guangzhou, Guangzhou, PR China
| | - Yang Bai
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University Guangzhou, Guangzhou, PR China
| | - Jizheng Li
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University Guangzhou, Guangzhou, PR China
| | - Hao Chen
- Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University Guangzhou, Guangzhou, PR China
| | - Lei Wang
- Department of Colon & Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University Guangzhou, 26 Yuancun Erheng road, 510655 Guangzhou, PR China
| | - Jianping Wang
- Department of Colon & Rectum Surgery, The Sixth Affiliated Hospital of Sun Yat-Sen University (Guangdong Gastrointestinal and Anal Hospital), Sun Yat-Sen University Guangzhou, 26 Yuancun Erheng road, 510655 Guangzhou, PR China.
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14
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Tian Y, Wang L, Ou JHJ. Autophagy, a double-edged sword in hepatocarcinogenesis. Mol Cell Oncol 2015; 2:e1004968. [PMID: 27308502 PMCID: PMC4905348 DOI: 10.1080/23723556.2015.1004968] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 12/31/2014] [Accepted: 01/02/2015] [Indexed: 11/26/2022]
Abstract
Autophagy has opposite effects on hepatocarcinogenesis depending on whether it occurs before or after its onset. Autophagy prevents the initiation of hepatocarcinogenesis by suppressing oxidative stress and DNA damage. However, it also inhibits cell death and the expression of tumor suppressors to promote tumor progression once hepatocarcinogenesis has been initiated.
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Affiliation(s)
- Yongjun Tian
- Department of Molecular Microbiology and Immunology; University of Southern California Keck School of Medicine ; Los Angeles, CA, USA
| | - Linya Wang
- Department of Molecular Microbiology and Immunology; University of Southern California Keck School of Medicine ; Los Angeles, CA, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology; University of Southern California Keck School of Medicine ; Los Angeles, CA, USA
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15
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Ren T, Takahashi Y, Liu X, Loughran TP, Sun SC, Wang HG, Cheng H. HTLV-1 Tax deregulates autophagy by recruiting autophagic molecules into lipid raft microdomains. Oncogene 2015; 34:334-45. [PMID: 24362528 PMCID: PMC4067462 DOI: 10.1038/onc.2013.552] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 10/14/2013] [Accepted: 11/01/2013] [Indexed: 12/13/2022]
Abstract
The retroviral oncoprotein Tax from human T-cell leukemia virus type 1 (HTLV-1), an etiological factor that causes adult T-cell leukemia and lymphoma, has a crucial role in initiating T-lymphocyte transformation by inducing oncogenic signaling activation. We here report that Tax is a determining factor for dysregulation of autophagy in HTLV-1-transformed T cells and Tax-immortalized CD4 memory T cells. Tax facilitated autophagic process by activating inhibitor of κB (IκB) kinase (IKK) complex, which subsequently recruited an autophagy molecular complex containing Beclin1 and Bif-1 to the lipid raft microdomains. Tax engaged a crosstalk between IKK complex and autophagic molecule complex by directly interacting with both complexes, promoting assembly of LC3+ autophagosomes. Moreover, expression of lipid raft-targeted Bif-1 or Beclin1 was sufficient to induce formation of LC3+ autophagosomes, suggesting that Tax recruitment of autophagic molecules to lipid rafts is a dominant strategy to deregulate autophagy in the context of HTLV-1 transformation of T cells. Furthermore, depletion of autophagy molecules such as Beclin1 and PI3 kinase class III resulted in impaired growth of HTLV-1-transformed T cells, indicating a critical role of Tax-deregulated autophagy in promoting survival and transformation of virally infected T cells.
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Affiliation(s)
- Tong Ren
- Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
- Department of Microbiology and Immunology, Penn State University College of Medicine, Hershey, PA 17033
| | - Yoshinori Takahashi
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033
| | - Xin Liu
- Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
| | - Thomas P. Loughran
- Penn State Hershey Cancer Institute, Penn State University College of Medicine, Hershey, PA 17033
| | - Shao-Cong Sun
- Department of Immunology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030
| | - Hong-Gang Wang
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033
| | - Hua Cheng
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201
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16
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Tian Y, Kuo CF, Sir D, Wang L, Govindarajan S, Petrovic LM, Ou JHJ. Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis. Cell Death Differ 2014; 22:1025-34. [PMID: 25526090 DOI: 10.1038/cdd.2014.201] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 10/05/2014] [Accepted: 11/05/2014] [Indexed: 12/29/2022] Open
Abstract
The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N-acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC.
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Affiliation(s)
- Y Tian
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - C-F Kuo
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - D Sir
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - L Wang
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - S Govindarajan
- 1] Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA [2] Rancho Los Amigos Rehabilitation Center, Downey, CA, USA
| | - L M Petrovic
- Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - J-H J Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
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17
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Qi Y, Li H, Zhang M, Zhang T, Frank J, Chen G. Autophagy in arsenic carcinogenesis. ACTA ACUST UNITED AC 2014; 66:163-8. [DOI: 10.1016/j.etp.2014.01.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Revised: 01/10/2014] [Accepted: 01/20/2014] [Indexed: 12/31/2022]
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Abstract
The common clear cell subtype of renal cell carcinoma is associated with hereditary or acquired loss of function of the von Hippel-Lindau tumor suppressor, a key component in oxygen sensing, perpetuating a stressed state. Autophagy is primarily a highly conserved, catabolic process by which stressed cells shuttle damaged or effete organelles and proteins into autophagosomes for sequestration and digestion after fusion with lysosomes. Autophagy is directed by autophagy-related genes and is divided into 4 discrete steps: initiation, nucleation, maturation, and degradation. During early tumorigenesis, apoptosis is enhanced and autophagy is suppressed, allowing accumulation of mutations and emergence of genomic instability. Late, an "autophagic switch" occurs, promoting survival and limiting apoptosis. Compounds such as chloroquine and hydroxychloroquine that prevent acidification of the lysosomal compartment are the sole clinically available inhibitors of autophagy. Currently, there are more than 30 trials examining combinations of hydroxychloroquine with anticancer agents. The intricate effects of autophagy on the immune response complicate manipulation of autophagy as part of the antitumor strategy. Further understanding of basic mechanisms of renal cell carcinoma pathogenesis and of autophagy will enable development of the next generation of pharmacologic modulators of autophagy.
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19
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Poillet L, Pernodet N, Boyer-Guittaut M, Adami P, Borg C, Jouvenot M, Delage-Mourroux R, Despouy G. QSOX1 inhibits autophagic flux in breast cancer cells. PLoS One 2014; 9:e86641. [PMID: 24475161 PMCID: PMC3901705 DOI: 10.1371/journal.pone.0086641] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 12/13/2013] [Indexed: 12/23/2022] Open
Abstract
The QSOX1 protein (Quiescin Sulfhydryl oxidase 1) catalyzes the formation of disulfide bonds and is involved in the folding and stability of proteins. More recently, QSOX1 has been associated with tumorigenesis and protection against cellular stress. It has been demonstrated in our laboratory that QSOX1 reduces proliferation, migration and invasion of breast cancer cells in vitro and reduces tumor growth in vivo. In addition, QSOX1 expression has been shown to be induced by oxidative or ER stress and to prevent cell death linked to these stressors. Given the function of QSOX1 in these two processes, which have been previously linked to autophagy, we wondered whether QSOX1 might be regulated by autophagy inducers and play a role in this catabolic process. To answer this question, we used in vitro models of breast cancer cells in which QSOX1 was overexpressed (MCF-7) or extinguished (MDA-MB-231). We first showed that QSOX1 expression is induced following amino acid starvation and maintains cellular homeostasis. Our results also indicated that QSOX1 inhibits autophagy through the inhibition of autophagosome/lysosome fusion. Moreover, we demonstrated that inhibitors of autophagy mimic the effect of QSOX1 on cell invasion, suggesting that its role in this process is linked to the autophagy pathway. Previously published data demonstrated that extinction of QSOX1 promotes tumor growth in NOG mice. In this study, we further demonstrated that QSOX1 null tumors present lower levels of the p62 protein. Altogether, our results demonstrate for the first time a role of QSOX1 in autophagy in breast cancer cells and tumors.
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Affiliation(s)
- Laura Poillet
- Université de Franche-Comté, Estrogènes, Expression Génique et Pathologies du Système Nerveux Central, U.F.R. Sciences et Techniques, Besançon, Doubs, France
| | - Nicolas Pernodet
- Université de Franche-Comté, Estrogènes, Expression Génique et Pathologies du Système Nerveux Central, U.F.R. Sciences et Techniques, Besançon, Doubs, France
| | - Michaël Boyer-Guittaut
- Université de Franche-Comté, Estrogènes, Expression Génique et Pathologies du Système Nerveux Central, U.F.R. Sciences et Techniques, Besançon, Doubs, France
| | - Pascale Adami
- Université de Franche-Comté, Estrogènes, Expression Génique et Pathologies du Système Nerveux Central, U.F.R. Sciences et Techniques, Besançon, Doubs, France
| | - Christophe Borg
- Université de Franche-Comté, Inserm UMR 1098, Relation Hôte Greffon et Ingénierie Cellulaire et Génique, Besançon, Doubs, France
| | - Michèle Jouvenot
- Université de Franche-Comté, Estrogènes, Expression Génique et Pathologies du Système Nerveux Central, U.F.R. Sciences et Techniques, Besançon, Doubs, France
| | - Régis Delage-Mourroux
- Université de Franche-Comté, Estrogènes, Expression Génique et Pathologies du Système Nerveux Central, U.F.R. Sciences et Techniques, Besançon, Doubs, France
| | - Gilles Despouy
- Université de Franche-Comté, Estrogènes, Expression Génique et Pathologies du Système Nerveux Central, U.F.R. Sciences et Techniques, Besançon, Doubs, France
- * E-mail:
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20
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Ko YH, Cho YS, Won HS, An HJ, Sun DS, Hong SU, Park JH, Lee MA. Stage-stratified analysis of prognostic significance of Bax-interacting factor-1 expression in resected colorectal cancer. BIOMED RESEARCH INTERNATIONAL 2013; 2013:329839. [PMID: 24175288 PMCID: PMC3794616 DOI: 10.1155/2013/329839] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 08/27/2013] [Accepted: 08/27/2013] [Indexed: 01/03/2023]
Abstract
BACKGROUND/AIM Bax-interacting factor-1 (Bif-1) plays a crucial role in apoptosis and autophagy. The aim of this study was to evaluate Bif-1 protein expression and its prognostic significance in colorectal cancer (CRC). METHODS We analyzed Bif-1 protein expression in 251 resected specimens from patients with CRC by immunohistochemistry using tissue microarray. RESULTS Low Bif-1 expression was observed in 131 patients (52.2%) and high Bif-1 expression in 120 patients (47.8%). No significant differences were observed in clinicopathological parameters between patients with high and low Bif-1 expression. Kaplan-Meier survival analysis showed no difference in survival between patients with high and low Bif-1 expression. Stratified analysis of Bif-1 according to TNM stage demonstrated that low Bif-1 expression was significantly associated with a poor outcome in patients with stages I and II (P = 0.034). Stratified multivariate analysis demonstrated that low Bif-1 expression was an independent indicator of poor prognosis (hazard ratio, 0.459; 95% confidence interval, 0.285-0.739; P = 0.001). CONCLUSION Patients with low levels of Bif-1 expression have shortened survival rates in CRC of stages I and II. This suggests that Bif-1 protein expression may be a useful prognostic marker in early-stage CRC.
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Affiliation(s)
- Yoon Ho Ko
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Young-Seok Cho
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Hye Sung Won
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Ho Jung An
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Der Sheng Sun
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu 480-717, Republic of Korea
| | - Soon Uk Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
| | - Jin Hee Park
- Department of Biomedical Science, The Catholic University of Korea College of Medicine, Seoul 137-701, Republic of Korea
| | - Myung Ah Lee
- Department of Internal Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul 137-701, Republic of Korea
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21
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Yu KN, Kim JE, Seo HW, Chae C, Cho MH. Differential toxic responses between pristine and functionalized multiwall nanotubes involve induction of autophagy accumulation in murine lung. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART A 2013; 76:1282-1292. [PMID: 24283420 DOI: 10.1080/15287394.2013.850137] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Carbon nanotubes (CNT) are becoming commonly used in industrial applications. However, the toxicity associated with this material remains to be established. The aim of this study was to investigate the potential toxic mechanisms associated with multiwall carbon nanotubes (MWCNT) in normal mouse lung. A total of 100 μg of two types of MWCNT, namely, pristine MWCNT (PMWCNT) and acid-treated-MWCNT (TMWCNT), was administered to male C57BL/6 mice via intratracheal (IT) instillation for a period of 6 mo. Our results indicated that PMWCNT induced pulmonary autophagy accumulation and resulted in more potent tumorigenic effects compared to TMWCNT. Accordingly, MWCNT may exert differential toxicity attributed to various physicochemical properties. Data emphasize the need for careful regulation of production and use of CNT.
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Affiliation(s)
- Kyeong-Nam Yu
- a Laboratory of Toxicology, College of Veterinary Medicine , Seoul National University , Seoul , Korea
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22
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Fernandez Larrosa PN, Alvarado CV, Rubio MF, Ruiz Grecco M, Micenmacher S, Martinez-Noel GA, Panelo L, Costas MA. Nuclear receptor coactivator RAC3 inhibits autophagy. Cancer Sci 2012; 103:2064-71. [PMID: 22957814 DOI: 10.1111/cas.12019] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2012] [Revised: 08/16/2012] [Accepted: 08/23/2012] [Indexed: 12/16/2022] Open
Abstract
RAC3 is an oncogene naturally overexpressed in several tumors. Besides its role as coactivator, it can exert several protumoral cytoplasmic actions. Autophagy was found to act either as a tumor suppressor during the early stages of tumor development, or as a protector of the tumor cell in later stages under hypoxic conditions. We found that RAC3 overexpression inhibits autophagy when induced by starvation or rapamycin and involves RAC3 nuclear translocation-dependent and -independent mechanisms. Moreover, hypoxia inhibits the RAC3 gene expression leading to the autophagy process, allowing tumor cells to survive until angiogenesis occurs. The interplay between RAC3, hypoxia, and autophagy could be an important mechanism for tumor progression and a good target for a future anticancer therapy.
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23
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Milla Sanabria L, Rodríguez ME, Cogno IS, Rumie Vittar NB, Pansa MF, Lamberti MJ, Rivarola VA. Direct and indirect photodynamic therapy effects on the cellular and molecular components of the tumor microenvironment. Biochim Biophys Acta Rev Cancer 2012; 1835:36-45. [PMID: 23046998 DOI: 10.1016/j.bbcan.2012.10.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Revised: 09/28/2012] [Accepted: 10/01/2012] [Indexed: 12/31/2022]
Abstract
Photodynamic therapy (PDT) is a novel cancer treatment. It involves the activation of a photosensitizer (PS) with light of specific wavelength, which interacts with molecular oxygen to generate singlet oxygen and other reactive oxygen species (ROS) that lead to tumor cell death. When a tumor is treated with PDT, in addition to affect cancer cells, the extracellular matrix and the other cellular components of the microenvironment are altered and finally this had effects on the tumor cells survival. Furthermore, the heterogeneity in the availability of nutrients and oxygen in the different regions of a tridimensional tumor has a strong impact on the sensitivity of cells to PDT. In this review, we summarize how PDT affects indirectly to the tumor cells, by the alterations on the extracellular matrix, the cell adhesion and the effects over the immune response. Also, we describe direct PDT effects on cancer cells, considering the intratumoral role that autophagy mediated by hypoxia-inducible factor 1 (HIF-1) has on the efficiency of the treatment.
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Affiliation(s)
- Laura Milla Sanabria
- Department of Molecular Biology, National University of Río Cuarto, Río Cuarto (5800), Córdoba, Argentina
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24
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Abstract
Autophagy is an evolutionarily conserved catabolic pathway that has multiple roles in carcinogenesis and cancer therapy. It can inhibit the initiation of tumorigenesis through limiting cytoplasmic damage, genomic instability and inflammation, and the loss of certain autophagy genes can lead to cancer. Conversely, autophagy can also assist cells in dealing with stressful metabolic environments, thereby promoting cancer cell survival. In fact, some cancers rely on autophagy to survive and progress. Furthermore, tumour cells can exploit autophagy to cope with the cytotoxicity of certain anticancer drugs. By contrast, it appears that certain therapeutics require autophagy for the effective killing of cancer cells. Despite these dichotomies, it is clear that autophagy has an important, if complex, role in cancer. This is further exemplified by the fact that autophagy is connected with major cancer networks, including those driven by p53, mammalian target of rapamycin (mTOR), RAS and glutamine metabolism. In this Commentary, we highlight recent advances in our understanding of the role that autophagy has in cancer and discuss current strategies for targeting autophagy for therapeutic gain.
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Affiliation(s)
- Emma Y Liu
- Tumour Cell Death Laboratory, Beatson Institute for Cancer Research, Garscube Estate, Glasgow, UK
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25
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Roesly HB, Khan MR, Chen HDR, Hill KA, Narendran N, Watts GS, Chen X, Dvorak K. The decreased expression of Beclin-1 correlates with progression to esophageal adenocarcinoma: the role of deoxycholic acid. Am J Physiol Gastrointest Liver Physiol 2012; 302:G864-G872. [PMID: 22301112 PMCID: PMC3355563 DOI: 10.1152/ajpgi.00340.2011] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Accepted: 01/19/2012] [Indexed: 01/31/2023]
Abstract
Beclin-1 has a central role in the regulation of autophagy. Barrett's esophagus (BE) is associated with a significantly increased risk for the development of esophageal adenocarcinoma (EAC). In the current study, we evaluated the role of Beclin-1 and autophagy in the EAC. Biopsies obtained from patients with BE and EAC, tissues from a rat model of BE and EAC, and esophageal cell lines were evaluated for the expression of Beclin-1 by immunohistochemistry, immunoblotting, or RT-PCR. Since reflux of bile acids is important in EAC, we also evaluated the effect of exposure to deoxycholic acid (DCA) on autophagy and Beclin-1 expression. Beclin-1 expression was high in squamous epithelium and nondysplastic BE, whereas its expression was low in dysplastic BE and EAC. The same pattern of expression was observed in rat tissues and in esophageal cell lines. Normal esophageal epithelium and HET-1A cells (derived from normal squamous epithelium) show high levels of Beclin-1, but lower levels of Beclin-1 were found in BE and EAC cell lines (CP-A, CP-C, and OE33). Acute exposure to DCA led to increased Beclin-1 expression and increased autophagy as evaluated by electron microscopy and counting percentage of GFP-LC3-positive BE cells with punctate pattern. In contrast, chronic exposure to DCA did not result in the alteration of Beclin-1 levels or autophagy. In summary, these data suggest that autophagy is initially activated in response to bile acids, but chronic exposure to bile acids leads to decreased Beclin-1 expression and autophagy resistance.
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Affiliation(s)
- Heather B Roesly
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85724, USA
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26
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Andrianasolo EH, Haramaty L, McPhail KL, White E, Vetriani C, Falkowski P, Lutz R. Bathymodiolamides A and B, ceramide derivatives from a deep-sea hydrothermal vent invertebrate mussel, Bathymodiolus thermophilus. JOURNAL OF NATURAL PRODUCTS 2011; 74:842-6. [PMID: 21222464 PMCID: PMC3081957 DOI: 10.1021/np100601w] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Two ceramide derivatives, bathymodiolamides A (1) and B (2), were isolated from the deep-sea hydrothermal vent invertebrate mussel Bathymodiolus thermophilus. The molecular structures of these compounds were determined using a combination of NMR spectroscopy, mass spectrometry, and chemical degradation. Biological activities were assessed in a ApopScreen cell-based screen for apoptosis induction and potential anticancer activity. To our knowledge, this is the first report of secondary metabolites from the marine hydrothermal vent mussel B. thermophilus.
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Affiliation(s)
- Eric H. Andrianasolo
- Center for Marine Biotechnology, Institute of Marine and Coastal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8521, United States
| | - Liti Haramaty
- Center for Marine Biotechnology, Institute of Marine and Coastal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8521, United States
| | - Kerry L. McPhail
- Department of Pharmaceutical Sciences, Oregon State University, Corvallis, Oregon 97331, United States
| | - Eileen White
- Center for Advanced Biotechnology and Medicine, Department of Molecular Biology and Biochemistry, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854, United States
- University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, United States
- The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, United States
| | - Costantino Vetriani
- Center for Marine Biotechnology, Institute of Marine and Coastal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8521, United States
| | - Paul Falkowski
- Center for Marine Biotechnology, Institute of Marine and Coastal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8521, United States
| | - Richard Lutz
- Center for Marine Biotechnology, Institute of Marine and Coastal Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901-8521, United States
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Abstract
Invasive, genetically abnormal carcinoma progenitor cells have been propagated from human and mouse breast ductal carcinoma in situ (DCIS) lesions, providing new insights into breast cancer progression. The survival of DCIS cells in the hypoxic, nutrient-deprived intraductal niche could promote genetic instability and the derepression of the invasive phenotype. Understanding potential survival mechanisms, such as autophagy, that might be functioning in DCIS lesions provides strategies for arresting invasion at the pre-malignant stage. A new, open trial of neoadjuvant therapy for patients with DCIS constitutes a model for testing investigational agents that target malignant progenitor cells in the intraductal niche.
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Affiliation(s)
- Virginia Espina
- George Mason University, Center for Applied Proteomics and Molecular Medicine, Manassas, Virginia 20110, USA
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28
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Autophagy genes as tumor suppressors. Curr Opin Cell Biol 2009; 22:226-33. [PMID: 19945837 DOI: 10.1016/j.ceb.2009.11.003] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2009] [Accepted: 11/05/2009] [Indexed: 12/13/2022]
Abstract
Autophagy, originally described as a universal lysosome-dependent bulk degradation of cytoplasmic components upon nutrient deprivation, has since been shown to influence diverse aspects of homeostasis and is implicated in a wide variety of pathological conditions, including cancer. The list of autophagy-related (Atg) genes associated with the initiation and progression of human cancer as well as with responses to cancer therapy continues to grow as these genes are being discovered. However, whether Atg genes work through their expected mechanisms of autophagy regulation and/or through as-yet-undefined functions in the development of cancer remains to be further clarified. Here we review recent advances in the knowledge of the molecular basis of autophagy genes and their biological outputs during tumor development. A better understanding of the mechanistic link between cellular autophagy and tumor growth control may ultimately better human cancer treatments.
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29
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Abstract
Macroautophagy (autophagy) is a lysosomal degradation pathway for the breakdown of intracellular proteins and organelles. Although constitutive autophagy is a homeostatic mechanism for intracellular recycling and metabolic regulation, autophagy is also stress responsive, in which it is important for the removal of damaged proteins and organelles. Autophagy thereby confers stress tolerance, limits damage, and sustains viability under adverse conditions. Autophagy is a tumor-suppression mechanism, yet it enables tumor cell survival in stress. Reconciling how loss of a prosurvival function can promote tumorigenesis, emerging evidence suggests that preservation of cellular fitness by autophagy may be key to tumor suppression. As autophagy is such a fundamental process, establishing how the functional status of autophagy influences tumorigenesis and treatment response is important. This is especially critical as many current cancer therapeutics activate autophagy. Therefore, efforts to understand and modulate the autophagy pathway will provide new approaches to cancer therapy and prevention.
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Affiliation(s)
- Eileen White
- The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903
- Department of Molecular Biology and Biochemistry, 604 Allison Road, Rutgers University, Piscataway, NJ 08854
| | - Robert S. DiPaola
- The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903
- Division of Medical Oncology, Department of Internal Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08903
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