|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Walweel N, Aydin O. Enhancing Therapeutic Efficacy in Cancer Treatment: Integrating Nanomedicine with Autophagy Inhibition Strategies. ACS OMEGA 2024; 9:27832-27852. [PMID: 38973850 PMCID: PMC11223161 DOI: 10.1021/acsomega.4c02234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/01/2024] [Accepted: 05/30/2024] [Indexed: 07/09/2024]
Abstract
The complicated stepwise lysosomal degradation process known as autophagy is in charge of destroying and eliminating damaged organelles and defective cytoplasmic components. This mechanism promotes metabolic adaptability and nutrition recycling. Autophagy functions as a quality control mechanism in cells that support homeostasis and redox balance under normal circumstances. However, the role of autophagy in cancer is controversial because, mostly depending on the stage of the tumor, it may either suppress or support the disease. While autophagy delays the onset of tumors and slows the dissemination of cancer in the early stages of tumorigenesis, numerous studies demonstrate that autophagy promotes the development and spread of tumors as well as the evolution and development of resistance to several anticancer drugs in advanced cancer stages. In this Review, we primarily emphasize the therapeutic role of autophagy inhibition in improving the treatment of multiple cancers and give a broad overview of how its inhibition modulates cancer responses. There have been various attempts to inhibit autophagy, including the use of autophagy inhibitor drugs, gene silencing therapy (RNA interference), and nanoparticles. In this Review, all these topics are thoroughly covered and illustrated by recent studies and field investigations.
Collapse
Affiliation(s)
- Nada Walweel
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
| | - Omer Aydin
- Department
of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey
- NanoThera
Lab, ERFARMA-Drug Application and Research Center, Erciyes University, Kayseri 38280, Turkey
- ERNAM-Nanotechnology
Research and Application Center, Erciyes
University, Kayseri 38039, Turkey
- ERKAM-Clinical-Engineering
Research and Implementation Center, Erciyes
University, Kayseri 38030, Turkey
| |
Collapse
|
|
3
|
Drug Resistance in Colorectal Cancer: From Mechanism to Clinic. Cancers (Basel) 2022; 14:cancers14122928. [PMID: 35740594 PMCID: PMC9221177 DOI: 10.3390/cancers14122928] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
Collapse
|
|
4
|
Qu J, Lin Z. Autophagy Regulation by Crosstalk between miRNAs and Ubiquitination System. Int J Mol Sci 2021; 22:ijms222111912. [PMID: 34769343 PMCID: PMC8585084 DOI: 10.3390/ijms222111912] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are non-coding single-stranded RNA molecules encoded by endogenous genes with ~22 nucleotides which are involved in the regulation of post-transcriptional gene expression. Ubiquitination and deubiquitination are common post-translational modifications in eukaryotic cells and important pathways in regulating protein degradation and signal transduction, in which E3 ubiquitin ligases and deubiquitinases (DUBs) play a decisive role. MiRNA and ubiquitination are involved in the regulation of most biological processes, including autophagy. Furthermore, in recent years, the direct interaction between miRNA and E3 ubiquitin ligases or deubiquitinases has attracted much attention, and the cross-talk between miRNA and ubiquitination system has been proved to play key regulatory roles in a variety of diseases. In this review, we summarized the advances in autophagy regulation by crosstalk between miRNA and E3 ubiquitin ligases or deubiquitinases.
Collapse
|
|
5
|
Cui D, Ma J, Liang T, Sun L, Meng L, Liang T, Li Q. Selenium nanoparticles fabricated in laminarin polysaccharides solutions exert their cytotoxicities in HepG2 cells by inhibiting autophagy and promoting apoptosis. Int J Biol Macromol 2019; 137:829-835. [DOI: 10.1016/j.ijbiomac.2019.07.031] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 06/11/2019] [Accepted: 07/04/2019] [Indexed: 01/14/2023]
|
|
6
|
Pan X, Chen Y, Shen Y, Tantai J. Knockdown of TRIM65 inhibits autophagy and cisplatin resistance in A549/DDP cells by regulating miR-138-5p/ATG7. Cell Death Dis 2019; 10:429. [PMID: 31160576 PMCID: PMC6546683 DOI: 10.1038/s41419-019-1660-8] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 04/10/2019] [Accepted: 04/30/2019] [Indexed: 12/24/2022]
Abstract
Cisplatin resistance is the main cause of treatment failure in patients with non-small-cell lung cancer (NSCLC). Autophagy is a key mechanism of resistance to chemotherapy. Given that tripartite motif (TRIM)-containing proteins are involved in the regulation of autophagy and chemoresistance, we aimed to study the functions of TRIM protein members in autophagy-mediated chemoresistance of NSCLC. We found that TRIM65 was significantly increased in cisplatin-resistant NSCLC cell line (A549/DDP) as compared to the parental cell line (A549). Knockdown of TRIM65 can enhance cisplatin-induced apoptosis and inhibit autophagy in A549/DDP cells, as indicated by Annexin V/PI staining, caspase3 activity test, and LC3-II immunofluorescence staining. Additionally, knockdown of TRIM65 significantly decreased the expression of an important autophagy mediator, ATG7, which was a potential target of miR-138-5p. miR-138-5p inhibitor significantly abolished the effects of TRIM65 knockdown on autophagy and cisplatin-induced apoptosis. Moreover, TRIM65 induced the ubiquitination and degradation of TNRC6A, resulting in the suppressed expression of miR-138-5p. TRIM65 knockdown inhibited the growth of tumors derived from A549/DDP cells. Furthermore, cisplatin-resistant NSCLC tissues displayed higher expression of TRIM65 mRNA and lower expression of miR-138-5p as compared to cisplatin non-resistant ones. miR-138-5p expression was negatively correlated with TRIM65 mRNA in NSCLC tissues. Collectively, the present study indicates that TRIM65 knockdown attenuates autophagy and cisplatin resistance in A549/DDP cells via regulating miR-138-5p.
Collapse
Affiliation(s)
- Xufeng Pan
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yong Chen
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Yuzhou Shen
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Jicheng Tantai
- Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
| |
Collapse
|
|
7
|
Dong X, Yang Y, Zhou Y, Bi X, Zhao N, Zhang Z, Li L, Hang Q, Zhang R, Chen D, Cao P, Yin Z, Luo L. Glutathione S-transferases P1 protects breast cancer cell from adriamycin-induced cell death through promoting autophagy. Cell Death Differ 2019; 26:2086-2099. [PMID: 30683915 DOI: 10.1038/s41418-019-0276-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 12/19/2018] [Accepted: 12/20/2018] [Indexed: 12/31/2022] Open
Abstract
Glutathione S-transferases P1 (GSTP1) is a phase II detoxifying enzyme and increased expression of GSTP1 has been linked with acquired resistance to anti-cancer drugs. However, most anticancer drugs are not good substrates for GSTP1, suggesting that the contribution of GSTP1 to drug resistances might not be dependent on its capacity to detoxify chemicals or drugs. In the current study, we found a novel mechanism by which GSTP1 protects human breast cancer cells from adriamycin (ADR)-induced cell death and contributes to the drug resistance. GSTP1 protein level is very low in human breast cancer cell line MCF-7 but is high in ADR-resistant MCF-7/ADR cells. Under ADR treatment, MCF-7/ADR cells showed a higher autophagy level than MCF-7 cells. Overexpression of GSTP1 in MCF-7 cells by using the DNA transfection vector enhanced autophagy and down-regulation of GSTP1 through RNA interference in MCF-7/ADR cells decreased autophagy. When autophagy was prevented, GSTP1-induced ADR resistance reduced. We found that GSTP1 enhanced autophagy level in MCF-7 cells through interacting with p110α subunit of phosphatidylinositol-3-kinase (PI3K) and then inhibited PI3K/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) activity. Proline123, leucine160, and glutamine163, which located in C terminal of GSTP1, are essential for GSTP1 to interact with p110α, and the following autophagy and drug resistance regulation. Taken together, our findings demonstrate that high level of GSTP1 maintains resistance of breast cancer cells to ADR through promoting autophagy. These new molecular insights provide an important contribution to our better understanding the effect of GSTP1 on the resistance of tumors to chemotherapy.
Collapse
Affiliation(s)
- Xiaoliang Dong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Yang Yang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.,Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.,Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Yi Zhou
- Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, China
| | - Xiaowen Bi
- Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, China
| | - Ningwei Zhao
- Shimadzu Biomedical Research Laboratory, Shanghai, 200233, China.,Laboratory of Pharmacology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Zhengping Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.,Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, 210042, China
| | - Ling Li
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Qiyun Hang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Ruhui Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Dan Chen
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
| | - Peng Cao
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.,Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, 210028, China
| | - Zhimin Yin
- Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, Jiangsu, China.
| | - Lan Luo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
| |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
Ma J, Weng L, Wang Z, Jia Y, Liu B, Wu S, Cao Y, Sun X, Yin X, Shang M, Mao A. MiR-124 induces autophagy-related cell death in cholangiocarcinoma cells through direct targeting of the EZH2-STAT3 signaling axis. Exp Cell Res 2018. [PMID: 29530475 DOI: 10.1016/j.yexcr.2018.02.037] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma (CCA) is a lethal cancer associated with chronic inflammation that has increased in prevalence in recent decades. The dysregulated expression of microRNAs (miRNAs) has been detected in various types of malignancies, and depending on the target genes this can result in miRNAs functioning as tumor suppressors or oncogenes. In this study, we investigated the role of miR-124 in cholangiocarcinoma (CCA) and found that its expression was significantly downregulated in the tumor tissue of patients and in CCA cell lines. Our results provided evidence that miR-124 induces apoptotic cell death and triggers the autophagic flux in CCA cells. EZH2 and STAT3 were identified as direct targets of miR-124. The effect of miR-124 on EZH2 expression in CCA cells was evaluated using cell transfection, xenotransplantation into nude mice and a luciferase reporter assay. Silencing of EZH2 restored the effects of miR-124, whereas overexpression of EZH2 abrogated the effects of miR-124. Silencing of Beclin1 or ATG5 abrogated the effects of miR-124 or siEZH2. In vivo, overexpression of miR-124 dramatically induced autophagy-related cell death and suppressed tumorigenicity. Taken together, our findings indicated that downregulation of miR-124 expression was associated with disease progression in human CCA and we revealed that miR-124 exerts a tumor suppressive function in CCA by inducing autophagy-related cell death via direct targeting of the EZH2-STAT3 signaling axis.
Collapse
Affiliation(s)
- Jun Ma
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China
| | - Li Weng
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China.
| | - Zhongmin Wang
- Affiliated Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, China.
| | - Yiping Jia
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China
| | - Bingyan Liu
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China
| | - Shaoqiu Wu
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China
| | - Yan Cao
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China
| | - Xianjun Sun
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China
| | - Xiang Yin
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China
| | - Mingyi Shang
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China.
| | - Aiwu Mao
- Tongren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xian Xia Road, Shanghai 200336, China.
| |
Collapse
|
|
10
|
Chen SY, Lin CH, Lin JT, Cheng YF, Chen HM, Kao SH. Adenine causes cell cycle arrest and autophagy of chronic myelogenous leukemia K562 cells via AMP-activated protein kinase signaling. Oncol Lett 2017; 14:5575-5580. [PMID: 29113185 DOI: 10.3892/ol.2017.6890] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 05/11/2017] [Indexed: 01/14/2023] Open
Abstract
AMP-activated protein kinase (AMPK) is known as a pivotal regulator of cellular metabolism. Mounting evidences have demonstrated that AMPK activation exerts tumor suppressive activity on leukemia cells. The present study reported that adenine, an AMPK activator, triggers cell cycle arrest and autophagy of human chronic myelogenous leukemia K562 cells consequently suppressing cell viability. The present findings revealed that adenine treatment (4.0-8.0 mM) significantly inhibited the viability of K562 cells to 69.3±2.5% (24 h) and 53.4±2.1% (48 h) of the control. Flow cytometric analysis revealed that there was a significant accumulation in G2/M phase, but not sub-G1 phase K562 cells following exposure to adenine. Additional investigation demonstrated that adenine treatments significantly increased the number of acidic vesicular organelles and the level of autophagosomal microtubule associated protein 1 light chain 3 α (LC3) marker. By contrast, cleavage of caspase-9, caspase-3 and poly-ADP-ribose polymerase was insignificantly affected in K562 cells following adenine treatment. In K562 cells, adenine was able to markedly promote the phosphorylation of AMPKα and suppress the phosphorylation of mammalian target of rapamycin (mTOR), a downstream target of AMPK. In addition, inhibiting AMPK phosphorylation using dorsomorphin restored mTOR phosphorylation, inhibited the accumulation of LC3 and significantly recovered the suppressed cell viability in response to adenine. Taken together, the present results demonstrated that adenine induced G2/M phase arrest and autophagic cell death, consequently suppressing the viability of K562 cells, which may attribute to the AMPK activation triggered by adenine. These findings provide evidence that adenine may be beneficial to chronic myelogenous leukemia therapy by suppressing excessive cell proliferation.
Collapse
Affiliation(s)
- San-Yuan Chen
- Department of Traditional Chinese Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi 600, Taiwan R.O.C
| | - Chun-Hsiang Lin
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 402, Taiwan R.O.C
| | - Jiun-Tsai Lin
- Institute of Applied Science and Engineering, Catholic Fu Jen University, New Taipei 242, Taiwan R.O.C
| | - Yi-Fang Cheng
- Energenesis Biomedical Co. Ltd., New Taipei 235, Taiwan R.O.C
| | - Han-Min Chen
- Institute of Applied Science and Engineering, Catholic Fu Jen University, New Taipei 242, Taiwan R.O.C
| | - Shao-Hsuan Kao
- Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung 402, Taiwan R.O.C.,Clinical Laboratory, Chung Shan Medical University Hospital, Taichung 402, Taiwan R.O.C
| |
Collapse
|
|
11
|
Zhong JT, Yu J, Wang HJ, Shi Y, Zhao TS, He BX, Qiao B, Feng ZW. Effects of endoplasmic reticulum stress on the autophagy, apoptosis, and chemotherapy resistance of human breast cancer cells by regulating the PI3K/AKT/mTOR signaling pathway. Tumour Biol 2017; 39:1010428317697562. [PMID: 28459209 DOI: 10.1177/1010428317697562] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Nowadays, although chemotherapy is an established therapy for breast cancer, the molecular mechanisms of chemotherapy resistance in breast cancer remain poorly understood. This study aims to explore the effects of endoplasmic reticulum stress on autophagy, apoptosis, and chemotherapy resistance in human breast cancer cells by regulating PI3K/AKT/mTOR signaling pathway. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was performed to detect the cell viability of six human breast cancer cell lines (MCF-7, ZR-75-30, T47D, MDA-MB-435s, MDA-MB-453, and MDA-MB-231) treated with tunicamycin (5 µM), after which MCF-7 cells were selected for further experiment. Then, MCF-7 cells were divided into the control (without any treatment), tunicamycin (8 µ), BEZ235 (5 µ), and tunicamycin + BEZ235 groups. Cell viability of each group was testified by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Western blotting was applied to determine the expressions of endoplasmic reticulum stress and PI3K/AKT/mTOR pathway-related proteins and autophagy- and apoptosis-related proteins. Monodansylcadaverine and Annexin V-fluorescein isothiocyanate/propidium iodide staining were used for determination of cell autophagy and apoptosis. Furthermore, MCF-7 cells were divided into the control (without any treatment), tunicamycin (5 µM), cisplatin (16 µM), cisplatin (16 µM) + BEZ235 (5 µM), tunicamycin (5 µM) + cisplatin (16 µM), and tunicamycin (5 µM) + cisplatin (16 µM) + BEZ235 groups. Cell viability and apoptosis were also evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Annexin V-fluorescein isothiocyanate/propidium iodide staining. In MCF-7 cells treated with tunicamycin, cell viability decreased significantly, but PEAK, eIF2, and CHOP were upregulated markedly and p-PI3K, p-AKT, and p-MTOR were downregulated in dose- and time-dependent manners. In the tunicamycin + BEZ235 group, the cell viability was lower and the apoptosis rate was higher than those of the control and monotherapy groups. Compared with the cisplatin group, the tunicamycin + cisplatin group showed a relatively higher growth inhibition rate; the growth inhibition rate substantially increased in the tunicamycin + cisplatin + BEZ235 group than the tunicamycin + cisplatin group. The apoptosis rate was highest in tunicamycin + cisplatin + BEZ235 group, followed by tunicamycin + cisplatin group and then cisplatin group. Our study provide evidence that endoplasmic reticulum stress activated by tunicamycin could promote breast cancer cell autophagy and apoptosis and enhance chemosensitivity of MCF-7 cells by inhibiting the PI3K/AKT/mTOR signaling pathway.
Collapse
Affiliation(s)
- Jia-Teng Zhong
- 1 Department of Pathology, Xinxiang Medical University, Xinxiang, P.R. China
| | - Jian Yu
- 2 Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, P.R. China
| | - Hai-Jun Wang
- 1 Department of Pathology, Xinxiang Medical University, Xinxiang, P.R. China
| | - Yu Shi
- 3 School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, P.R. China
| | - Tie-Suo Zhao
- 4 Department of Immunology, Xinxiang Medical University, Xinxiang, P.R. China
| | - Bao-Xia He
- 5 Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| | - Bin Qiao
- 5 Department of Urology, China-Japan Union Hospital of Jilin University, Changchun, P.R. China
| | - Zhi-Wei Feng
- 3 School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, P.R. China
| |
Collapse
|
|
12
|
Abstract
Autophagy is a self-digestive process regulated by an intricate network of factors able either to ensure the prosurvival function of autophagy or to convert it in a death pathway. Recently, the involvement of miRNAs in the regulation of autophagy networks has been reported. This review will summarize the main features of these small noncoding endogenous RNAs, focusing on their relevance in cancer and finally addressing their impact on autophagy.
Collapse
|
|
13
|
Yang Y, Dai C, Cai Z, Hou A, Cheng D, Wu G, Li J, Cui J, Xu D. The Pathway Analysis of Micrornas Regulated Drug-Resistant Responses in HeLa Cells. IEEE Trans Nanobioscience 2016; 15:113-8. [DOI: 10.1109/tnb.2016.2539365] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|
|
14
|
Guamán Ortiz LM, Croce AL, Aredia F, Sapienza S, Fiorillo G, Syeda TM, Buzzetti F, Lombardi P, Scovassi AI. Effect of new berberine derivatives on colon cancer cells. Acta Biochim Biophys Sin (Shanghai) 2015; 47:824-33. [PMID: 26341980 DOI: 10.1093/abbs/gmv077] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 06/11/2015] [Indexed: 12/22/2022] Open
Abstract
The natural alkaloid berberine has been recently described as a promising anticancer drug. In order to improve its efficacy and bioavailability, several derivatives have been designed and synthesized and found to be even more potent than the lead compound. Among the series of berberine derivatives we have produced, five compounds were identified to be able to heavily affect the proliferation of human HCT116 and SW613-B3 colon carcinoma cell lines. Remarkably, these active compounds exhibit high fluorescence emission property and ability to induce autophagy.
Collapse
Affiliation(s)
- Luis Miguel Guamán Ortiz
- Istituto di Genetica Molecolare CNR, Pavia 27100, Italy Departamento de Ciencias de la Salud, Universidad Técnica Particular de Loja, Loja, Ecuador
| | | | - Francesca Aredia
- Istituto di Genetica Molecolare CNR, Pavia 27100, Italy Dipartimento di Biologia e Biotecnologie 'L. Spallanzani', Università degli Studi di Pavia, Pavia, Italy
| | | | | | | | | | | | | |
Collapse
|
|
15
|
Dinić J, Ranđelović T, Stanković T, Dragoj M, Isaković A, Novaković M, Pešić M. Chemo-protective and regenerative effects of diarylheptanoids from the bark of black alder (Alnus glutinosa) in human normal keratinocytes. Fitoterapia 2015; 105:169-76. [DOI: 10.1016/j.fitote.2015.07.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/30/2015] [Accepted: 07/02/2015] [Indexed: 01/15/2023]
|
|
16
|
Abstract
Autophagy, a catabolic process, is activated by conditions of stress and nutrient deprivation, which occurs to maintain metabolic homeostasis by performing catabolic lysis of excessive or unnecessary proteins, and injured or aged organelles. Autophagy is regulated by various signaling pathways. Main regulators of autophagy are the PI3K-Akt-mTOR pathway, Beclin1, Bcl-2, Ras and p53. Autophagy plays dual role in cancer, shows both tumor suppressive and oncogenic activity. It is accepted that drug resistance in cancer cells can be overcome by inhibition of autophagy. Herein, we summarize autophagy as a potential target of anticancer drugs and targeting autophagy provides a promising therapeutic strategy to circumvent resistance and enhance the effect of anticancer therapies for cancer patients.
Collapse
|
|
17
|
ARHI (DIRAS3)-mediated autophagy-associated cell death enhances chemosensitivity to cisplatin in ovarian cancer cell lines and xenografts. Cell Death Dis 2015; 6:e1836. [PMID: 26247722 PMCID: PMC4558501 DOI: 10.1038/cddis.2015.208] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 05/24/2015] [Accepted: 06/26/2015] [Indexed: 11/08/2022]
Abstract
Autophagy can sustain or kill tumor cells depending upon the context. The mechanism of autophagy-associated cell death has not been well elucidated and autophagy has enhanced or inhibited sensitivity of cancer cells to cytotoxic chemotherapy in different models. ARHI (DIRAS3), an imprinted tumor suppressor gene, is downregulated in 60% of ovarian cancers. In cell culture, re-expression of ARHI induces autophagy and ovarian cancer cell death within 72 h. In xenografts, re-expression of ARHI arrests cell growth and induces autophagy, but does not kill engrafted cancer cells. When ARHI levels are reduced after 6 weeks, dormancy is broken and xenografts grow promptly. In this study, ARHI-induced ovarian cancer cell death in culture has been found to depend upon autophagy and has been linked to G1 cell-cycle arrest, enhanced reactive oxygen species (ROS) activity, RIP1/RIP3 activation and necrosis. Re-expression of ARHI enhanced the cytotoxic effect of cisplatin in cell culture, increasing caspase-3 activation and PARP cleavage by inhibiting ERK and HER2 activity and downregulating XIAP and Bcl-2. In xenografts, treatment with cisplatin significantly slowed the outgrowth of dormant autophagic cells after reduction of ARHI, but the addition of chloroquine did not further inhibit xenograft outgrowth. Taken together, we have found that autophagy-associated cancer cell death and autophagy-enhanced sensitivity to cisplatin depend upon different mechanisms and that dormant, autophagic cancer cells are still vulnerable to cisplatin-based chemotherapy.
Collapse
|
|
18
|
Wang Z, Wang N, Liu P, Chen Q, Situ H, Xie T, Zhang J, Peng C, Lin Y, Chen J. MicroRNA-25 regulates chemoresistance-associated autophagy in breast cancer cells, a process modulated by the natural autophagy inducer isoliquiritigenin. Oncotarget 2015; 5:7013-26. [PMID: 25026296 PMCID: PMC4196180 DOI: 10.18632/oncotarget.2192] [Citation(s) in RCA: 190] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Recent findings have revealed that dysregulated miRNAs contribute significantly to autophagy and chemoresistance. Pharmacologically targeting autophagy-related miRNAs is a novel strategy to reverse drug resistance. Here, we report a novel function of isoliquiritigenin (ISL) as a natural inhibitor of autophagy-related miR-25 in killing drug-resistant breast cancer cells. ISL induced chemosensitization, cell cycle arrest and autophagy, but not apoptosis, in MCF-7/ADR cells. ISL also promoted the degradation of the ATP-binding cassette (ABC) protein ABCG2 primarily via the autophagy-lysosome pathway. More importantly, miRNA 3.0 array experiments identified miR-25 as the main target of ISL in triggering autophagy flux. A mechanistic study validated that miR-25 inhibition led to autophagic cell death by directly increasing ULK1 expression, an early regulator in the autophagy induction phase. miR-25 overexpression was demonstrated to block ISL-induced autophagy and chemosensitization. Subsequent in vivo experiments showed that ISL had chemosensitizing potency, as revealed by an increase in LC3-II staining, the downregulation of ABCG2, a reduction in miR-25 expression and the activation of the miR-25 target ULK1. Overall, our results not only indicate that ISL acts as a natural autophagy inducer to increase breast cancer chemosensitivity, but also reveal that miR-25 functions as a novel regulator of autophagy by targeting ULK1.
Collapse
Affiliation(s)
- Zhiyu Wang
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine; School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; These authors contributed equally to this work
| | - Neng Wang
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; These authors contributed equally to this work
| | - Pengxi Liu
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine
| | - Qianjun Chen
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine
| | - Honglin Situ
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine
| | - Ting Xie
- Department of Dermatology, Guangdong Provincial Hospital of Chinese Medicine, The Second Clinical Collage of Guangzhou University of Chinese Medicine
| | - Jianxing Zhang
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine
| | - Cheng Peng
- Deapartment of Pharmacology, Chengdu University of Traditional Chinese Medicine
| | - Yi Lin
- Department of Mammary Disease, Guangdong Provincial Hospital of Chinese Medicine
| | - Jianping Chen
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| |
Collapse
|
|
19
|
Lu C, Wang W, Jia Y, Liu X, Tong Z, Li B. Inhibition of AMPK/autophagy potentiates parthenolide-induced apoptosis in human breast cancer cells. J Cell Biochem 2015; 115:1458-66. [PMID: 24619908 DOI: 10.1002/jcb.24808] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 03/10/2014] [Indexed: 12/25/2022]
Abstract
Parthenolide is the main bioactive component in feverfew, a common used herbal medicine, and has been extensively studied in relation to its anti-cancer properties. However there have been very few in-depth studies of the activities of this compound at the molecular level. Here, we showed that parthenolide increased reactive oxygen species (ROS), induced cell death, activated AMPK and autophagy, and led to M phase cell cycle arrest in breast cancer cells. Removal of ROS inhibited all parthenolide-associated events, such as cell death, AMPK activation, autophagy induction, and cell cycle arrest. Blockade of autophagy relieved cell cycle arrest, whereas inhibition of AMPK activity significantly repressed the induction of both autophagy and cell cycle arrest. These observations clearly showed that parthenolide-driven ROS activated AMPK-autophagy pathway. Furthermore, inhibition of either AMPK or autophagy significantly potentiated parthenolide-induced apoptosis. Therefore, our results show that parthenolide activates both apoptosis pathway and AMPK-autophagy survival pathway through the generation of ROS, and that suppression of AMPK or autophagy can potentially enhance the anti-cancer effect of parthenolide on breast cancer cells.
Collapse
Affiliation(s)
- Can Lu
- Laboratory of Cancer Cell Biology, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P.R. China; Department of Breast Oncology, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, P.R. China
| | | | | | | | | | | |
Collapse
|
|
20
|
Wang B, Feng D, Han L, Fan J, Zhang X, Wang X, Ye L, Shi X, Feng M. Combination of apolipoprotein A1-modi liposome-doxorubicin with autophagy inhibitors overcame drug resistance in vitro. J Pharm Sci 2014; 103:3994-4004. [PMID: 25354472 DOI: 10.1002/jps.24216] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2014] [Revised: 08/25/2014] [Accepted: 09/22/2014] [Indexed: 12/15/2022]
Abstract
Multidrug resistance (MDR) represents the major drawback in chemotherapy. Liposome-based approaches could reverse MDR to some extent through circumventing the active efflux effect of P-glycoprotein. However, the reverse power of liposome is very limited because the nontargeting liposome is inefficient to deliver drugs to tumor actively. Besides, autophagy could reinforce the resistance of tumor cells to the cytotoxicity of intracellular drugs. Here, liposomal doxorubicin (Lipodox) that was conjugated with apolipoprotein A1-apo-Lipodox, was employed in tumor targeting delivery of doxorubicin. In the experiments, apo-Lipodox could enter cells effectively and reverse MDR more efficiently than their nontargeting counterpart. Autophagy occurred in this process and contributed to the survival of tumor cells. Combination use of autophagy inhibitors could enhance the cytotoxicity of apo-Lipodox and reverse drug resistance to a higher degree. We propose that this strategy holds promise to overcome MDR in human cancer.
Collapse
Affiliation(s)
- Baolong Wang
- Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
| | - Duo Feng
- The Sixth People's Hospital of Shenzhen, Shenzhen, Guangdong 201203, People's Republic of China
| | - Lei Han
- Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
| | - Jiajun Fan
- Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
| | | | - Xin Wang
- Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
| | - Li Ye
- Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
| | - Xunlong Shi
- Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China
| | - Meiqing Feng
- Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai 201203, People's Republic of China.
| |
Collapse
|
|
21
|
Abstract
Amiloride derivatives are a class of new promising chemotherapeutic agents. A representative member of this family is the sodium-hydrogen antiporter inhibitor HMA (5-(N,N-hexamethylene amiloride), which has been demonstrated to induce cellular intracytosolic acidification and cell death through the apoptotic pathway(s). This work aims at characterizing drug response of human cancer cell lines to HMA. After a first screening revealing that HMA interferes with cancer cell survival, we focused our attention on SW613-B3 colon carcinoma cells, which are intrinsically resistant to a panel of drugs. Searching for the activation of canonical apoptosis, we found that this process was abortive, given that the final steps of this process, i.e. PARP-1 cleavage and DNA ladder, were not detectable. Thus, we addressed caspase-independent paradigms of cell death and we observed that HMA promotes the induction of the LEI/L-DNase II pathway as well as of parthanatos. Finally, we explored the possible impact of autophagy of cell response to HMA, providing the evidence that autophagy is activated in our experimental system. On the whole, our results defined the biochemical reactions triggered by HMA, and elucidated its multiple effects, thus adding further complexity to the intricate network leading to drug resistance.
Collapse
|
|
22
|
Long DX, Hu D, Wang P, Wu YJ. Induction of autophagy in human neuroblastoma SH-SY5Y cells by tri-ortho-cresyl phosphate. Mol Cell Biochem 2014; 396:33-40. [PMID: 24990248 DOI: 10.1007/s11010-014-2139-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2014] [Accepted: 06/17/2014] [Indexed: 01/24/2023]
Abstract
Tri-ortho-cresyl phosphate (TOCP) is an organophosphorus ester and has been widely used in industry. It is found that TOCP induced delayed neurotoxicity in humans and sensitive animal species. However, the mechanism of TOCP-induced neural cytotoxicity remains unclear. In this study, we studied whether autophagy is involved in TOCP-induced neural cytotoxicity in human neuroblastoma SH-SY5Y cells. We found that 0.5 and 1.0 mM TOCP treatment significantly increased the ectopic accumulation of microtubule-associated protein 1 light chain 3 (LC3)-immunopositive puncta, Beclin 1, and LC3-II/LC3-I levels in SH-SY5Y cells in a dose-dependent manner. Notably, by monodansylcadaverine staining method, we found abundant punctate fluorescent acidic vesicular organelles in TOCP-treated cells. Furthermore, ultrastructural observation under the transmission electron microscope indicated that the cytoplasm was occupied by autophagosomes in TOCP-treated SH-SY5Y cells. Thus, these results suggest that TOCP may induce autophagy, and autophagy may be involved in the development of TOCP-induced neural cytotoxicity.
Collapse
Affiliation(s)
- Ding-Xin Long
- Laboratory of Molecular Toxicology, State Key Laboratory of Integrated Management of Pest Insects and Rodents, Institute of Zoology, Chinese Academy of Sciences, 1-5 Beichenxi Road, Beijing, 100101, People's Republic of China
| | | | | | | |
Collapse
|
|
23
|
Zhang W, Wu H, Liu L, Zhu Y, Chen Q. Phosphorylation Events in Selective Mitophagy: Possible Biochemical Markers? CURRENT PATHOBIOLOGY REPORTS 2013. [DOI: 10.1007/s40139-013-0033-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
|
|
24
|
Chen S, Han Q, Wang X, Yang M, Zhang Z, Li P, Chen A, Hu C, Li S. IBP-mediated suppression of autophagy promotes growth and metastasis of breast cancer cells via activating mTORC2/Akt/FOXO3a signaling pathway. Cell Death Dis 2013; 4:e842. [PMID: 24113176 PMCID: PMC3824689 DOI: 10.1038/cddis.2013.380] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 08/27/2013] [Accepted: 08/28/2013] [Indexed: 01/04/2023]
Abstract
Interferon regulatory factor-4 binding protein (IBP) is a novel upstream activator of Rho GTPases. Our previous studies have shown that ectopic expression of IBP was correlated with malignant behaviors of human breast cancer cells, and invasive human breast cancer had high expression of IBP that promoted the proliferation of these cells. However, it remains unknown whether autophagy inhibition contributes to IBP-mediated tumorigenesis. In this study, we for the first time, reported that upregulation of IBP expression significantly suppressed the autophagy of breast cancer cells, and downregulation of IBP expression markedly induced autophagy of these cells. Further investigation revealed that IBP effectively counteracted autophagy by directly activating mammalian target of rapamycin complex 2 (mTORC2) and upregulating phosphorylation of Akt on ser473 and FOXO3a on Thr32. Moreover, IBP-mediated suppression of autophagy was dependent on mTORC2/Akt/FOXO3a signaling pathway. Finally, our results demonstrated that IBP-mediated breast cancer cell growth in vitro and in vivo was strongly correlated with suppression of mTORC2-dependent autophagy. These findings suggest that the anti-autophagic property of IBP has an important role in IBP-mediated tumorigenesis, and IBP may serve as an attractive target for treatment of breast cancer.
Collapse
Affiliation(s)
- S Chen
- Department of Clinical Biochemistry, Southwestern Hospital, Third Military Medical University, No. 30 Gaotanyan Street, Shapingba District, Chongqing 400038, PR China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Forward: combating resistance: infectious diseases. Future Med Chem 2013; 5:1175-6. [PMID: 23859196 DOI: 10.4155/fmc.13.105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
|
|
26
|
|