|
1
|
Ayub A, Hasan MK, Mahmud Z, Hossain MS, Kabir Y. Dissecting the multifaceted roles of autophagy in cancer initiation, growth, and metastasis: from molecular mechanisms to therapeutic applications. Med Oncol 2024; 41:183. [PMID: 38902544 DOI: 10.1007/s12032-024-02417-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 05/28/2024] [Indexed: 06/22/2024]
Abstract
Autophagy is a cytoplasmic defense mechanism that cells use to break and reprocess their intracellular components. This utilization of autophagy is regarded as a savior in nutrient-deficient and other stressful conditions. Hence, autophagy keeps contact with and responds to miscellaneous cellular tensions and diverse pathways of signal transductions, such as growth signaling and cellular death. Importantly, autophagy is regarded as an effective tumor suppressor because regular autophagic breakdown is essential for cellular maintenance and minimizing cellular damage. However, paradoxically, autophagy has also been observed to promote the events of malignancies. This review discussed the dual role of autophagy in cancer, emphasizing its influence on tumor survival and progression. Possessing such a dual contribution to the malignant establishment, the prevention of autophagy can potentially advocate for the advancement of malignant transformation. In contrast, for the context of the instituted tumor, the agents of preventing autophagy potently inhibit the advancement of the tumor. Key regulators, including calpain 1, mTORC1, and AMPK, modulate autophagy in response to nutritional conditions and stress. Oncogenic mutations like RAS and B-RAF underscore autophagy's pivotal role in cancer development. The review also delves into autophagy's context-dependent roles in tumorigenesis, metastasis, and the tumor microenvironment (TME). It also discusses the therapeutic effectiveness of autophagy for several cancers. The recent implication of autophagy in the control of both innate and antibody-mediated immune systems made it a center of attention to evaluating its role concerning tumor antigens and treatments of cancer.
Collapse
Affiliation(s)
- Afia Ayub
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh
| | - Md Kamrul Hasan
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh.
- Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main St. W., Hamilton, L8S 4K1, Canada.
- Department of Public Health, North South University, Dhaka, Bangladesh.
| | - Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
| | - Md Sabbir Hossain
- Department of Biochemistry and Molecular Biology, Tejgaon College, National University, Gazipur, 1704, Bangladesh
| | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
| |
Collapse
|
|
2
|
McPhee M, Lee J, Salsman J, Pinelli M, Di Cara F, Rosen K, Dellaire G, Ridgway ND. Nuclear lipid droplets in Caco2 cells originate from nascent precursors and in situ at the nuclear envelope. J Lipid Res 2024; 65:100540. [PMID: 38570093 PMCID: PMC11077042 DOI: 10.1016/j.jlr.2024.100540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/05/2024] Open
Abstract
Intestinal epithelial cells convert excess fatty acids into triglyceride (TAG) for storage in cytoplasmic lipid droplets and secretion in chylomicrons. Nuclear lipid droplets (nLDs) are present in intestinal cells but their origin and relationship to cytoplasmic TAG synthesis and secretion is unknown. nLDs and related lipid-associated promyelocytic leukemia structures (LAPS) were abundant in oleate-treated Caco2 but less frequent in other human colorectal cancer cell lines and mouse intestinal organoids. nLDs and LAPS in undifferentiated oleate-treated Caco2 cells harbored the phosphatidate phosphatase Lipin1, its product diacylglycerol, and CTP:phosphocholine cytidylyltransferase (CCT)α. CCTα knockout Caco2 cells had fewer but larger nLDs, indicating a reliance on de novo PC synthesis for assembly. Differentiation of Caco2 cells caused large nLDs and LAPS to form regardless of oleate treatment or CCTα expression. nLDs and LAPS in Caco2 cells did not associate with apoCIII and apoAI and formed dependently of microsomal triglyceride transfer protein expression and activity, indicating they are not derived from endoplasmic reticulum luminal LDs precursors. Instead, undifferentiated Caco2 cells harbored a constitutive pool of nLDs and LAPS in proximity to the nuclear envelope that expanded in size and number with oleate treatment. Inhibition of TAG synthesis did affect the number of nascent nLDs and LAPS but prevented their association with promyelocytic leukemia protein, Lipin1α, and diacylglycerol, which instead accumulated on the nuclear membranes. Thus, nLD and LAPS biogenesis in Caco2 cells is not linked to lipoprotein secretion but involves biogenesis and/or expansion of nascent nLDs by de novo lipid synthesis.
Collapse
Affiliation(s)
- Michael McPhee
- Depts of Pediatrics and Biochemistry & Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Jonghwa Lee
- Depts of Pediatrics and Biochemistry & Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Jayme Salsman
- Depts of Pathology and Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Marinella Pinelli
- Dept of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Francesca Di Cara
- Dept of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Kirill Rosen
- Depts of Pediatrics and Biochemistry & Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Graham Dellaire
- Depts of Pathology and Biochemistry & Molecular Biology, Dalhousie University, Halifax, Nova Scotia, Canada.
| | - Neale D Ridgway
- Depts of Pediatrics and Biochemistry & Molecular Biology, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia, Canada.
| |
Collapse
|
|
3
|
Huang Y, Zhen Y, Chen Y, Sui S, Zhang L. Unraveling the interplay between RAS/RAF/MEK/ERK signaling pathway and autophagy in cancer: From molecular mechanisms to targeted therapy. Biochem Pharmacol 2023; 217:115842. [PMID: 37802240 DOI: 10.1016/j.bcp.2023.115842] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/08/2023]
Abstract
RAS/RAF/MEK/ERK signaling pathway is one of the most important pathways of Mitogen-activated protein kinases (MAPK), which widely participate in regulating cell proliferation, differentiation, apoptosis and signaling transduction. Autophagy is an essential mechanism that maintains cellular homeostasis by degrading aged and damaged organelles. Recently, some studies revealed RAS/RAF/MEK/ERK signaling pathway is closely related to autophagy regulation and has a dual effect in tumor cells. However, the specific mechanism by which RAS/RAF/MEK/ERK signaling pathway participates in autophagy regulation is not fully understood. This article provides a comprehensive review of the research progress with regard to the RAS/RAF/MEK/ERK signaling pathway and autophagy, as well as their interplay in cancer therapy. The impact of small molecule inhibitors that target the RAS/RAF/MEK/ERK signaling pathway on autophagy is discussed in this study. The advantages and limitations of the clinical combination of these small molecule inhibitors with autophagy inhibitors are also explored. The findings from this study may provide additional perspectives for future cancer treatment strategies.
Collapse
Affiliation(s)
- Yunli Huang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Yongqi Zhen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yanmei Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shaoguang Sui
- Emergency Department, The Second Hospital, Dalian Medical University, Dalian 116000, China.
| | - Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
| |
Collapse
|
|
4
|
Liang Y, Wu D, Qu Q, Li Z, Yin H. MORC4 plays a tumor-promoting role in colorectal cancer via regulating PCGF1/CDKN1A axis in vitro and in vivo. Cancer Gene Ther 2023:10.1038/s41417-023-00605-2. [PMID: 36932196 DOI: 10.1038/s41417-023-00605-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 01/30/2023] [Accepted: 03/02/2023] [Indexed: 03/19/2023]
Abstract
MORC family CW-type zinc finger 4 (MORC4) possessing nuclear matrix binding domains has been observed to be involved in multiple cancer development. By digging three gene expression omnibus (GEO) gene microarrays (GSE110223, GSE110224 and GSE24514), we found that MORC4 was overexpressed in colorectal cancer (CRC) samples (log2 Fold change >1, p < 0.05). We aimed to investigate the role of MORC4 in CRC malignant behaviors, with an emphasis on polycomb group ring finger 1 (PCGF1)/cyclin-dependent kinase inhibitor 1A (CDKN1A) axis. Firstly, we confirmed MORC4 as an upregulated gene in 60 pairs of frozen CRC and adjacent normal samples. MORC4 overexpression increased proliferation and metastasis, and decreased apoptosis in SW480 and HT29 cells, which was diminished by the knockdown of PCGF1, a transcriptional repressor of CDKN1A (a potent cyclin-dependent kinase inhibitor). MORC4 was further identified as a novel molecule that interacted with PCGF1 via coimmunoprecipitation. MORC4 itself did not substantially suppress CDKN1A transcriptional activity, but it augmented PCGF1's effect on CDKN1A. Additionally, MORC4 acted as the substrate of HECT, C2, and WW domain-containing E3 ubiquitin protein ligase 2 (HECW2) and was degraded through ubiquitin-proteasome system. Collectively, our work suggested that MORC4 accelerated CRC progression via governing PCGF1/CDKN1A signaling.
Collapse
Affiliation(s)
- Yichao Liang
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
| | - Di Wu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
| | - Qiao Qu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
| | - Zhilong Li
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China
| | - Hongzhuan Yin
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, 110004, Liaoning, China.
| |
Collapse
|
|
5
|
Abstract
INTRODUCTION Calpain-1 and calpain-2 are prototypical classical isoforms of the calpain family of calcium-activated cysteine proteases. Their substrate proteins participate in a wide range of cellular processes, including transcription, survival, proliferation, apoptosis, migration, and invasion. Dysregulated calpain activity has been implicated in tumorigenesis, suggesting that calpains may be promising therapeutic targets. AREAS COVERED This review covers clinical and basic research studies implicating calpain-1 and calpain-2 expression and activity in tumorigenesis and metastasis. We highlight isoform specific functions and provide an overview of substrates and cancer-related signalling pathways affected by calpain-mediated proteolytic cleavage. We also discuss efforts to develop clinically relevant calpain specific inhibitors and spotlight the challenges facing inhibitor development. EXPERT OPINION Rationale for targeting calpain-1 and calpain-2 in cancer is supported by pre-clinical and clinical studies demonstrating that calpain inhibition has the potential to attenuate carcinogenesis and block metastasis of aggressive tumors. The wide range of substrates and cleavage products, paired with inconsistencies in model systems, underscores the need for more complete understanding of physiological substrates and how calpain cleavage alters their function in cellular processes. The development of isoform specific calpain inhibitors remains an important goal with therapeutic potential in cancer and other diseases.
Collapse
Affiliation(s)
- Ivan Shapovalov
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
| | - Danielle Harper
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
| | - Peter A Greer
- Department of Pathology and Molecular Medicine, Queen's University, Division of Cancer Biology and Genetics, Queen's Cancer Research Institute, 10 Stuart Street, Botterell Hall, Room A309, Kingston, Ontario, K7L 3N6 Canada
| |
Collapse
|
|
6
|
Schmukler E, Pinkas-Kramarski R. The interplay between Ras, Autophagy and cancer. ADVANCES IN CANCER BIOLOGY - METASTASIS 2021; 3:100014. [DOI: 10.1016/j.adcanc.2021.100014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
7
|
Wang S, Qian H, Zhang L, Liu P, Zhuang D, Zhang Q, Bai F, Wang Z, Yan Y, Guo J, Huang J, Wu X. Inhibition of Calcineurin/NFAT Signaling Blocks Oncogenic H-Ras Induced Autophagy in Primary Human Keratinocytes. Front Cell Dev Biol 2021; 9:720111. [PMID: 34350189 PMCID: PMC8328491 DOI: 10.3389/fcell.2021.720111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022] Open
Abstract
Mutations of H-Ras, a member of the RAS family, are preferentially found in cutaneous squamous cell carcinomas (SCCs). H-Ras has been reported to induce autophagy, which plays an essential role in tissue homeostasis in multiple types of cancer cells and in fibroblasts, however, the potential role of H-Ras in regulating autophagy in human keratinocytes has not been reported. In this study, we found that the stable expression of the G12V mutant of H-RAS (H-Ras G12V ) induced autophagy in human keratinocytes, and interestingly, the induction of autophagy was strongly blocked by inhibiting the calcineurin/nuclear factor of activated T cells (NFAT) pathway with either a calcineurin inhibitor (Cyclosporin A) or a NFAT inhibitor (VIVIT), or by the small interfering RNA (siRNA) mediated knockdown of calcineurin B1 or NFATc1 in vitro, as well as in vivo. To characterize the role of the calcineurin/NFAT pathway in H-Ras induced autophagy, we found that H-Ras G12V promoted the nuclear translocation of NFATc1, an indication of the activation of the calcineurin/NFAT pathway, in human keratinocytes. However, activation of NFATc1 either by the forced expression of NFATc1 or by treatment with phenformin, an AMPK activator, did not increase the formation of autophagy in human keratinocytes. Further study revealed that inhibiting the calcineurin/NFAT pathway actually suppressed H-Ras expression in H-Ras G12V overexpressing cells. Finally, chromatin immunoprecipitation (ChIP) assays showed that NFATc1 potentially binds the promoter region of H-Ras and the binding efficiency was significantly enhanced by the overexpression of H-Ras G12V , which was abolished by treatment with the calcineurin/NFAT pathway inhibitors cyclosporine A (CsA) or VIVIT. Taking these data together, the present study demonstrates that the calcineurin/NFAT signaling pathway controls H-Ras expression and interacts with the H-Ras pathway, involving the regulation of H-Ras induced autophagy in human keratinocytes.
Collapse
Affiliation(s)
- Shuangshuang Wang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Hua Qian
- Department of Stomatology, The Second Hospital of Shandong University, Jinan, China
| | - Liwei Zhang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Panpan Liu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China.,Department of Pediatric Dentistry, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Dexuan Zhuang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Qun Zhang
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Fuxiang Bai
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China
| | - Zhihong Wang
- Qilu Children's Hospital of Shandong University, Jinan, China
| | - Yonggan Yan
- Center for Advanced Jet Engineering Technologies, Key Laboratory of High Efficiency and Clean Mechanical Manufacture of Ministry of Education, School of Mechanical Engineering, Shandong University, Jinan, China
| | - Jing Guo
- Department of Orthodontics, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China.,Savaid Stomatology School of Hangzhou Medical College, Ningbo Stomatology Hospital, Ningbo, China
| | - Jun Huang
- Center for Advanced Jet Engineering Technologies, Key Laboratory of High Efficiency and Clean Mechanical Manufacture of Ministry of Education, School of Mechanical Engineering, Shandong University, Jinan, China
| | - Xunwei Wu
- Department of Tissue Engineering and Regeneration, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, China.,Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| |
Collapse
|
|
8
|
Comprehensive understanding of anchorage-independent survival and its implication in cancer metastasis. Cell Death Dis 2021; 12:629. [PMID: 34145217 PMCID: PMC8213763 DOI: 10.1038/s41419-021-03890-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 02/07/2023]
Abstract
Detachment is the initial and critical step for cancer metastasis. Only the cells that survive from detachment can develop metastases. Following the disruption of cell-extracellular matrix (ECM) interactions, cells are exposed to a totally different chemical and mechanical environment. During which, cells inevitably suffer from multiple stresses, including loss of growth stimuli from ECM, altered mechanical force, cytoskeletal reorganization, reduced nutrient uptake, and increased reactive oxygen species generation. Here we review the impact of these stresses on the anchorage-independent survival and the underlying molecular signaling pathways. Furthermore, its implications in cancer metastasis and treatment are also discussed.
Collapse
|
|
9
|
Tong CWS, Wu MMX, Yan VW, Cho WCS, To KKW. Repurposing loperamide to overcome gefitinib resistance by triggering apoptosis independent of autophagy induction in KRAS mutant NSCLC cells. Cancer Treat Res Commun 2020; 25:100229. [PMID: 33152554 DOI: 10.1016/j.ctarc.2020.100229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/17/2020] [Accepted: 10/23/2020] [Indexed: 12/01/2022]
Abstract
BACKGROUND Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for first-line treatment of non-small cell lung cancer (NSCLC) with sensitizing EGFR mutations. However, NSCLC patients bearing mutant KRAS are inherently unresponsive to gefitinib. Defective autophagy was proposed to mediate resistance to EGFR-TKIs. In this study, the reversal of primary resistance to gefitinib in NSCLC by putative autophagy inducers was investigated. MATERIALS AND METHODS A few putative autophagy inducers were investigated in NSCLC cells harboring KRAS or EGFR mutations. Quantitative real-time PCR and Western blot analysis were used to evaluate expression of autophagy-related genes and proteins. Sulforhodamine B assay was used to evaluate cytotoxicity of drug combinations. Flow cytometric asssays were used to study apoptotic and cell cycle effects. RESULTS The antidiarrheal agent loperamide was identified as an autophagy inducer. Loperamide promoted the formation of autophagosomes and it potentiated the cytotoxic effect of gefitinib specifically in NSCLC cells bearing mutant KRAS and wild-type EGFR. Gefitinib-loperamide combination enhanced apoptosis and G1 cell cycle arrest, both of which could not be reversed by pharmacological autophagy inhibitor (3-methyladenine). Moreover, synergistic anticancer effect of gefitinib-loperamide combination was observed in both autophagy-proficient (Atg5-wild type) and -deficient (Atg5-knockout) mouse embryonic fibroblasts. Loperamide overcome gefitinib resistance in NSCLC harboring mutant KRAS and wild-type EGFR through increased apoptosis but independent of autophagy induction. CONCLUSION Loperamide could be repurposed to overcome primary resistance to gefitinib in KRAS-mutation bearing NSCLC as it also helps relieve the common side effect of diarrhea caused by EGFR-TKIs.
Collapse
Affiliation(s)
- Christy W S Tong
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Mia M X Wu
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vivi W Yan
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William C S Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
| |
Collapse
|
|
10
|
Cheng Z, Xin H, Han T. BECN1 promotes the migration of NSCLC cells through regulating the ubiquitination of Vimentin. Cell Adh Migr 2020; 13:249-259. [PMID: 31272261 PMCID: PMC6629178 DOI: 10.1080/19336918.2019.1638690] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BECN1/Beclin1 is one of the key proteins in autophagy regulation. However, the biological functions of BECN1 in non-small cell lung cancer (NSCLC) were obscure. Here, we found that neither BECN1 knockdown nor overexpression affected the proliferation of NSCLC cells. Surprisingly, BECN1 overexpression increased cell migration and knocking down BECN1 significantly reduced the migratory ability of NSCLC cells. We further demonstrated that BECN1 could interact with Vimentin and affected its K48-linked ubiquitination. What’s more, BECN1 could also interact with ubiquitin-specific peptidase 14 (USP14), the key de-ubiquitinase of Vimentin, and regulated USP14 mediated de-ubiquitination of Vimentin. Thus, our studies revealed an oncosupportive role of BECN1 in the migration of NSCLC cells through regulating the ubiquitination of Vimentin.
Collapse
Affiliation(s)
- Zhujun Cheng
- a Jiangxi Institute of Respiratory Disease , The First Affiliated Hospital of Nanchang University , Nanchang , P.R. China.,b Department of Burn , The First Affiliated Hospital of Nanchang University , Nanchang , P.R. China.,c The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine , Nanchang University , Nanchang , P.R. China
| | - Hongbo Xin
- c The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine , Nanchang University , Nanchang , P.R. China
| | - Tianyu Han
- a Jiangxi Institute of Respiratory Disease , The First Affiliated Hospital of Nanchang University , Nanchang , P.R. China
| |
Collapse
|
|
11
|
The crosstalk between STAT3 and p53/RAS signaling controls cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy. Oncogenesis 2019; 8:59. [PMID: 31597912 PMCID: PMC6785561 DOI: 10.1038/s41389-019-0165-8] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 09/14/2019] [Accepted: 09/16/2019] [Indexed: 01/07/2023] Open
Abstract
Chemoresistance has been the biggest obstacle in ovarian cancer treatment, and STAT3 may play an important role in chemoresistance of multiple cancers, but the underlying mechanism of STAT3 in ovarian cancer chemoresistance has long been truly illusive, particularly in association with p53 and RAS signaling. In this study, by using wild type, constitutive active, and dominant negative STAT3 constructs, wild-type p53, and RAS-mutant V12, we performed a series of in vitro and in vivo experiments by gene overexpression, drug treatment, and animal assays. We found that phosphorylation of STAT3 Y705 but not S727 promoted cancer cell EMT and metastasis through the Slug-mediated regulation of E-cadherin and Vimentin. The phosphorylation of STAT3 at Y705 also activated the MAPK and PI3K/AKT signaling to inhibit the ERS-mediated autophagy through down-regulation of pPERK, pelf2α, ATF6α, and IRE1α, which led to increased cisplatin resistance. Induction of wild type p53 in STAT3-DN-transfected cells further diminished the chemoresistance and tumor growth through the upregulation of the MAPK- and PI3K/AKT-mediated ERS and autophagy. Introduction of STAT3-DN deprived the RASV12-induced ERS, autophagy, oncogenicity, and cisplatin resistance, whereas introduction of p53 in STAT3-DN/RASV12 expressing cells induced additional tumor retardation and cisplatin sensitivity. Thus, our data provide strong evidence that the crosstalk between STAT3 and p53/RAS signaling controls ovarian cancer cell metastasis and cisplatin resistance via the Slug/MAPK/PI3K/AKT-mediated regulation of EMT and autophagy.
Collapse
|
|
12
|
Zheng H, Yuan C, Zhang H, Chen Y, Zhang H. The tissue- and developmental stage-specific involvement of autophagy genes in aggrephagy. Autophagy 2019; 16:589-599. [PMID: 31204564 DOI: 10.1080/15548627.2019.1632121] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Genetic screens have identified two sets of genes that act at distinct steps of basal autophagy in higher eukaryotes: the pan-eukaryotic ATG genes and the metazoan-specific EPG genes. Very little is known about whether these core macroautophagy/autophagy genes are differentially employed during multicellular organism development. Here we analyzed the function of core autophagy genes in autophagic removal of SQST-1/SQSTM1 during C. elegans development. We found that loss of function of genes acting at distinct steps in the autophagy pathway causes different patterns of SQST-1 accumulation in different tissues and developmental stages. We also identified that the calpain protease clp-2 acts in a cell context-specific manner in SQST-1 degradation. clp-2 is required for degradation of SQST-1 in the hypodermis and neurons, but is dispensable in the body wall muscle and intestine. Our results indicate that autophagy genes are differentially employed in a tissue- and stage-specific manner during the development of multicellular organisms.Abbreviations: ATG: autophagy related; CLP: calpain family; EPG: ectopic PGL granules; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; LGG-1/LC3: LC3, GABARAP and GATE-16 family; MIT: microtubule interacting and transport; PGL: P granule abnormality protein; SQST-1: sequestosome-related; UPS: ubiquitin-proteasome system.
Collapse
Affiliation(s)
- Hui Zheng
- Department of Immunology, Peking University School of Basic Medical Science, Beijing, P.R. China.,National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China
| | - Chongzhen Yuan
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China
| | - Hui Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China
| | - Yingyu Chen
- Department of Immunology, Peking University School of Basic Medical Science, Beijing, P.R. China
| | - Hong Zhang
- National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P.R. China.,College of Life Sciences, University of Chinese Academy of Sciences, Beijing, P.R. China
| |
Collapse
|
|
13
|
Zhang Z, Chen J, Huang W, Ning D, Liu Q, Wang C, Zhang L, Ren L, Chu L, Liang H, Fan H, Zhang B, Chen X. FAM134B induces tumorigenesis and epithelial-to-mesenchymal transition via Akt signaling in hepatocellular carcinoma. Mol Oncol 2019; 13:792-810. [PMID: 30556279 PMCID: PMC6441892 DOI: 10.1002/1878-0261.12429] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 11/02/2018] [Accepted: 11/13/2018] [Indexed: 01/03/2023] Open
Abstract
Fam134b (JK-1, RETREG1) was first identified as an oncogene in esophageal squamous cell carcinoma. However, the roles of FAM134B during tumorigenesis of hepatocellular carcinoma (HCC) and in epithelial-to-mesenchymal transition (EMT) were previously unclear. In this study, we investigated the function of FAM134B in HCC and the related tumorigenesis mechanisms, as well as how FAM134B induces EMT. We detected the expression of FAM134B in a normal hepatic cell line, HCC cell lines, fresh specimens, and a HCC tissue microarray. A retrospective study of 122 paired HCC tissue microarrays was used to analyze the correlation between FAM134B and clinical features. Gain- and loss-of-function experiments, rescue experiments, Akt pathway activator/inhibitors, nude mice xenograft models, and nude mice lung metastasis models were used to determine the underlying mechanisms of FAM134B in inducing tumorigenesis and EMT in vitro and in vivo. The expression level of FAM134B was highly elevated in HCC, as compared with that in normal liver tissues and normal hepatic cells. Overexpression of FAM134B was significantly associated with tumor size (P = 0.025), pathological vascular invasion (P = 0.026), differentiation grade (P = 0.023), cancer recurrence (P = 0.044), and portal vein tumor thrombus (P = 0.036) in HCC. Patients with high expression of FAM134B had shorter overall survival and disease-free survival than patients with non-high expression of FAM134B. Furthermore, knockdown of FAM134B with shRNAs inhibited cell growth and motility, as well as tumor formation and metastasis in nude mice, all of which were promoted by overexpression of FAM134B. Our study demonstrated that Fam134b is an oncogene that plays a crucial role in HCC via the Akt signaling pathway with subsequent glycogen synthase kinase-3β phosphorylation, accumulation of β-catenin, and stabilization of Snail, which promotes tumorigenesis, EMT, and tumor metastasis in HCC.
Collapse
Affiliation(s)
- Zhao‐qi Zhang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Jin Chen
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Wan‐qiu Huang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Deng Ning
- Department of Biliary and Pancreatic SurgeryTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Qiu‐meng Liu
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Chao Wang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Long Zhang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Li Ren
- Department of Hepatopancreatobiliary SurgeryAffiliated Hospital of Qinghai UniversityXiningChina
| | - Liang Chu
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Hui‐fang Liang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Hai‐ning Fan
- Department of Hepatopancreatobiliary SurgeryAffiliated Hospital of Qinghai UniversityXiningChina
| | - Bi‐xiang Zhang
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| | - Xiao‐ping Chen
- Hepatic Surgery CenterTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- Key Laboratory of Organ TransplantationMinistry of Education and Ministry of Public HealthWuhanChina
- Clinical Medicine Research Center of Hepatic Surgery in Hubei ProvinceWuhanChina
| |
Collapse
|
|
14
|
Zhang L, Chen J, Ning D, Liu Q, Wang C, Zhang Z, Chu L, Yu C, Liang HF, Zhang B, Chen X. FBXO22 promotes the development of hepatocellular carcinoma by regulating the ubiquitination and degradation of p21. J Exp Clin Cancer Res 2019; 38:101. [PMID: 30808376 PMCID: PMC6390379 DOI: 10.1186/s13046-019-1058-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 01/27/2019] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND Deregulation of ubiquitin ligases is related to the malignant progression of human cancers. F-box only protein 22 (FBXO22), an F-box E3 ligase, is a member of the F-box protein family. However, the biological function of FBXO22 in HCC and the underlying molecular mechanisms are still unclear. In this study, we explored the role of FBXO22 in HCC and its mechanism of promoting tumor development. METHODS We examined the expression of FBXO22 in normal liver cell lines, HCC cell lines, HCC tissue microarrays and fresh specimens. The correlation between FBXO22 and clinical features was analyzed in a retrospective study of 110 pairs of HCC tissue microarrays. Univariate and multivariate survival analyses were used to explore the prognostic value of FBXO22 in HCC. At the same time, the correlation between the FBXO22 and p21 was also studied in HCC samples. Knock-down and overexpression experiments, CHX and Mg132 intervention experiments, ubiquitination experiments, rescue experiments and nude mouse xenograft models were used to determine the potential mechanism by which FBXO22 promotes tumorigenesis in vitro and in vivo. RESULTS The expression of FBXO22 in HCC tissues was significantly higher than in normal liver tissues. The overall survival rate and disease-free survival time of patients with high expression of FBXO22 were significantly shorter than those of patients with low expression of FBXO22. The high expression of FBXO22 in HCC tissues were significantly correlated with serum AFP (p = 0. 003, Pearson's chi-squared test), tumor size (p = 0. 019, Pearson's chi-squared test) and vascular invasion (p = 0. 031, Pearson's chi-squared test). Especially, Multivariate analysis showed that tumor size and the expression of FBXO22 were independent prognostic indicator of OS (95% CI: 1.077-5.157, P<0.05). Correlation analysis also showed that FBXO22 was negatively correlated with p21 in tissue microarrays (r = - 0.3788, P<0.001, Pearson correlation) and fresh specimens (r = - 0.4037, P<0.01, Pearson correlation). Moreover, both in vitro and in vivo experiments showed that knocking down FBXO22 expression could inhibit cell proliferation, while overexpression of FBXO22 promoted tumor formation. Furthermore, we identified that FBXO22 interacts with p21 by regulating protein stability and by influencing the ubiquitination process. A knockdown of FBXO22 decreased the ubiquitylation of p21, while overexpression enhanced it. CONCLUSIONS This study uncovered a new mechanism by which FBXO22 functions as an oncogene in HCC pathogenesis and progression by mediating the ubiquitination and degradation of p21. It was also found that tumor size and the expression of FBXO22 were independent prognostic indicator of OS and the expression of FBXO22 and p21 was negatively correlated in clinical samples. Our findings present a new perspective for understanding the development of HCC, which may provide a new target for the treatment and management of this challenging cancer.
Collapse
Affiliation(s)
- Long Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, College of Medicine, Shihezi University, Shihezi, Xinjiang 832008 People’s Republic of China
| | - Jin Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| | - Deng Ning
- Department of Biliary and Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 People’s Republic of China
| | - Qiumeng Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| | - Chao Wang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| | - Zhaoqi Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| | - Chengpeng Yu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| | - Hui-fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030 People’s Republic of China
| |
Collapse
|
|
15
|
The role of autophagy in colitis-associated colorectal cancer. Signal Transduct Target Ther 2018; 3:31. [PMID: 30510778 PMCID: PMC6265276 DOI: 10.1038/s41392-018-0031-8] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 10/04/2018] [Accepted: 10/17/2018] [Indexed: 12/12/2022] Open
Abstract
Autophagy is an evolutionarily conserved catabolic process that eliminates harmful components through lysosomal degradation. In addition to its role in maintaining cellular homeostasis, autophagy is critical to pathological processes, such as inflammation and cancer. Colitis-associated colorectal cancer (CAC) is a specific type of colorectal cancer that develops from long-standing colitis in inflammatory bowel disease (IBD) patients. Accumulating evidence indicates that autophagy of microenvironmental cells plays different but vital roles during tumorigenesis and CAC development. Herein, after summarizing the recent advances in understanding the role of autophagy in regulating the tumor microenvironment during different CAC stages, we draw the following conclusions: autophagy in intestinal epithelial cells inhibits colitis and CAC initiation but promotes CAC progression; autophagy in macrophages inhibits colitis, but its function on CAC is currently unclear; autophagy in neutrophils and cancer-associated fibroblasts (CAFs) promotes both colitis and CAC; autophagy in dendritic cells (DCs) and T cells represses both colitis and CAC; autophagy in natural killer cells (NKs) inhibits colitis, but promotes CAC; and autophagy in endothelial cells plays a controversial role in colitis and CAC. Understanding the role of autophagy in specific compartments of the tumor microenvironment during different stages of CAC may provide insight into malignant transformation, tumor progression, and combination therapy strategies for CAC.
Collapse
|
|
16
|
Koustas E, Sarantis P, Papavassiliou AG, Karamouzis MV. Upgraded role of autophagy in colorectal carcinomas. World J Gastrointest Oncol 2018; 10:367-369. [PMID: 30487948 PMCID: PMC6247107 DOI: 10.4251/wjgo.v10.i11.367] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/01/2018] [Accepted: 10/09/2018] [Indexed: 02/05/2023] Open
Abstract
Autophagy is a basic catabolic process closely associated with degradation of cellular components. The role of autophagy in colorectal cancer (CRC) remains controversial. The mechanism of autophagy has been identified as protecting mechanism against tumorigenesis by isolation of damaged organelles or as cytoprotective provides energy in hypoxic regions of CRC tumors. Mutations in proto-oncogenes, such as RAS and BRAF, have been associated with autophagy initiation through signaling pathways of BRAF/MEK/ERK and PI3K/AKT/mTOR. A combination therapy of chemotherapeutic agents and autophagy inhibitors such as hydroxychloroquine or immunotherapy might represent a major step that could be evaluated as a putative novel therapeutic strategy in CRC patients.
Collapse
Affiliation(s)
- Evangelos Koustas
- Division of Molecular Oncology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Panagiotis Sarantis
- Division of Molecular Oncology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Athanassios G Papavassiliou
- Division of Molecular Oncology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Michalis V Karamouzis
- Division of Molecular Oncology, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens 11527, Greece
| |
Collapse
|
|
17
|
González R, Molina-Ruiz FJ, Bárcena JA, Padilla CA, Muntané J. Regulation of Cell Survival, Apoptosis, and Epithelial-to-Mesenchymal Transition by Nitric Oxide-Dependent Post-Translational Modifications. Antioxid Redox Signal 2018; 29:1312-1332. [PMID: 28795583 DOI: 10.1089/ars.2017.7072] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
SIGNIFICANCE Nitric oxide (NO) is a physiopathological messenger generating different reactive nitrogen species (RNS) according to hypoxic, acidic and redox conditions. Recent Advances: RNS and reactive oxygen species (ROS) promote relevant post-translational modifications, such as nitrosation, nitration, and oxidation, in critical components of cell proliferation and death, epithelial-to-mesenchymal transition, and metastasis. CRITICAL ISSUES The pro- or antitumoral properties of NO are dependent on local concentration, redox state, cellular status, duration of exposure, and compartmentalization of NO generation. The increased expression of NO synthase has been associated with cancer progression. However, the experimental strategies leading to high intratumoral NO generation have been shown to exert antitumoral properties. The effect of NO and ROS on cell signaling is critically altered by factors modulating tumor progression such as oxygen content, metabolism, and inflammatory response. The review describes the alteration of key components involved in cell survival and death, metabolism, and metastasis induced by RNS- and ROS-related post-translational modifications. FUTURE DIRECTIONS The identification of the molecular targets affected by nitrosation, nitration, and oxidation, as well as their interactions with other post-translational modifications, will improve the understanding on the complex signaling and cell fate decision in cancer. The therapeutic NO-based strategies have to address the complex crosstalk among NO and ROS with regard to critical components affecting tumor cell survival, metabolism, and metastasis in the progression of cancer, as well as close interaction with ionizing radiation and chemotherapy.
Collapse
Affiliation(s)
- Raúl González
- 1 Institute of Biomedicine of Seville (IBiS), IBiS/"Virgen del Rocío" University Hospital/CSIC/University of Seville , Seville, Spain
| | - Francisco J Molina-Ruiz
- 1 Institute of Biomedicine of Seville (IBiS), IBiS/"Virgen del Rocío" University Hospital/CSIC/University of Seville , Seville, Spain
| | - J Antonio Bárcena
- 2 Department of Biochemistry and Molecular Biology, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), University of Córdoba , Córdoba, Spain
| | - C Alicia Padilla
- 2 Department of Biochemistry and Molecular Biology, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), University of Córdoba , Córdoba, Spain
| | - Jordi Muntané
- 3 Department of General Surgery, "Virgen del Rocío" University Hospital/IBiS/CSIC/University of Seville , Seville, Spain .,4 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd) , Madrid, Spain
| |
Collapse
|
|
18
|
Yoo BH, Khan IA, Koomson A, Gowda P, Sasazuki T, Shirasawa S, Gujar S, Rosen KV. Oncogenic RAS-induced downregulation of ATG12 is required for survival of malignant intestinal epithelial cells. Autophagy 2017; 14:134-151. [PMID: 28933585 DOI: 10.1080/15548627.2017.1370171] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Activating mutations of RAS GTPase contribute to the progression of many cancers, including colorectal carcinoma. So far, attempts to develop treatments of mutant RAS-carrying cancers have been unsuccessful due to insufficient understanding of the salient mechanisms of RAS signaling. We found that RAS downregulates the protein ATG12 in colon cancer cells. ATG12 is a mediator of autophagy, a process of degradation and reutilization of cellular components. In addition, ATG12 can kill cells via autophagy-independent mechanisms. We established that RAS reduces ATG12 levels in cancer cells by accelerating its proteasomal degradation. We further observed that RAS-dependent ATG12 loss in these cells is mediated by protein kinases MAP2K/MEK and MAPK1/ERK2-MAPK3/ERK1, known effectors of RAS. We also demonstrated that the reversal of the effect of RAS on ATG12 achieved by the expression of exogenous ATG12 in cancer cells triggers both apoptotic and nonapoptotic signals and efficiently kills the cells. ATG12 is known to promote autophagy by forming covalent complexes with other autophagy mediators, such as ATG5. We found that the ability of ATG12 to kill oncogenic RAS-carrying malignant cells does not require covalent binding of ATG12 to other proteins. In summary, we have identified a novel mechanism by which oncogenic RAS promotes survival of malignant intestinal epithelial cells. This mechanism is driven by RAS-dependent loss of ATG12 in these cells.
Collapse
Affiliation(s)
- Byong Hoon Yoo
- a Departments of Pediatrics and Department of Biochemistry and Molecular Biology , Atlantic Research Centre, Dalhousie University , Halifax , NS , Canada
| | - Iman Aftab Khan
- a Departments of Pediatrics and Department of Biochemistry and Molecular Biology , Atlantic Research Centre, Dalhousie University , Halifax , NS , Canada
| | - Ananda Koomson
- a Departments of Pediatrics and Department of Biochemistry and Molecular Biology , Atlantic Research Centre, Dalhousie University , Halifax , NS , Canada
| | - Pramod Gowda
- a Departments of Pediatrics and Department of Biochemistry and Molecular Biology , Atlantic Research Centre, Dalhousie University , Halifax , NS , Canada
| | | | - Senji Shirasawa
- c Department of Cell Biology , Faculty of Medicine, and Center for Advanced Molecular Medicine, Fukuoka University , Fukuoka , Japan
| | - Shashi Gujar
- d Department of Microbiology and Immunology , Dalhousie University , Halifax , NS , Canada
| | - Kirill V. Rosen
- a Departments of Pediatrics and Department of Biochemistry and Molecular Biology , Atlantic Research Centre, Dalhousie University , Halifax , NS , Canada
| |
Collapse
|
|
19
|
Khan IA, Yoo BH, Rak J, Rosen KV. Mek activity is required for ErbB2 expression in breast cancer cells detached from the extracellular matrix. Oncotarget 2017; 8:105383-105396. [PMID: 29285258 PMCID: PMC5739645 DOI: 10.18632/oncotarget.22194] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Accepted: 09/09/2017] [Indexed: 12/15/2022] Open
Abstract
Detachment of non-malignant epithelial cells from the extracellullar matrix (ECM) triggers their growth arrest and apoptosis. Conversely, carcinoma cells can grow without adhesion to the ECM. This capacity for anchorage-independent growth is thought to be critical for tumor progression. ErbB2/Her2 oncoprotein is overproduced by a significant fraction of breast cancers and promotes anchorage-independent tumor cell growth by poorly understood mechanisms. In an effort to understand them we found that in order to produce ErbB2, detached breast cancer cells require the activity of an ErbB2 effector protein kinase Mek and that Mek-driven ErbB2 expression is neccesary for anchorage-independent growth of such cells. We observed that Mek inhibition does not alter ErbB2 mRNA levels in detached cancer cells and that ErbB2 protein loss induced by this inhibition can be blocked by a lysosomal inhibitor. We also noticed that an increase of the density of cancer cells detached from the ECM downregulates a Mek effector protein kinase Erk and causes ErbB2 loss. Those cells that survive after ErbB2 loss display resistance to trastuzumab, an anti-ErbB2 antibody used for ErbB2-positive breast cancer treatment. Thus, Mek-induced ErbB2 stabilization in detached breast cancer cells is critical for their ability to grow anchorage-independently and their trastuzumab sensitivity.
Collapse
Affiliation(s)
- Iman A Khan
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Canada
| | - Byong H Yoo
- Department of Pediatrics, Dalhousie University, Halifax, Canada
| | - Janusz Rak
- Department of Pediatrics, McGill University, Montreal, Canada.,The Research Institute of the McGill University Health Centre, Montreal Children's Hospital, Montreal, Canada
| | - Kirill V Rosen
- Department of Biochemistry and Molecular Biology, Dalhousie University, Halifax, Canada.,Department of Pediatrics, Dalhousie University, Halifax, Canada
| |
Collapse
|
|
20
|
Torres A, Gubbiotti MA, Iozzo RV. Decorin-inducible Peg3 Evokes Beclin 1-mediated Autophagy and Thrombospondin 1-mediated Angiostasis. J Biol Chem 2017; 292:5055-5069. [PMID: 28174297 PMCID: PMC5377817 DOI: 10.1074/jbc.m116.753632] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 02/06/2017] [Indexed: 01/31/2023] Open
Abstract
We previously discovered that systemic delivery of decorin for treatment of breast carcinoma xenografts induces paternally expressed gene 3 (Peg3), an imprinted gene encoding a zinc finger transcription factor postulated to function as a tumor suppressor. Here we found that de novo expression of Peg3 increased Beclin 1 promoter activity and protein expression. This process required the full-length Peg3 as truncated mutants lacking either the N-terminal SCAN domain or the zinc fingers failed to translocate to the nucleus and promote Beclin 1 transcription. Importantly, overexpression of Peg3 in endothelial cells stimulated autophagy and concurrently inhibited endothelial cell migration and evasion from a 3D matrix. Mechanistically, we found that Peg3 induced the secretion of the powerful angiostatic glycoprotein Thrombospondin 1 independently of Beclin 1 transcriptional induction. Thus, we provide a new mechanism whereby Peg3 can simultaneously evoke autophagy in endothelial cells and attenuate angiogenesis.
Collapse
Affiliation(s)
- Annabel Torres
- From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Maria A Gubbiotti
- From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| | - Renato V Iozzo
- From the Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107
| |
Collapse
|
|
21
|
Graziano S, Gonzalo S. Mechanisms of oncogene-induced genomic instability. Biophys Chem 2016; 225:49-57. [PMID: 28073589 DOI: 10.1016/j.bpc.2016.11.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 11/17/2016] [Accepted: 11/18/2016] [Indexed: 01/08/2023]
Abstract
Activating mutations in oncogenes promote uncontrolled proliferation and malignant transformation. Approximately 30% of human cancers carry mutations in the RAS oncogene. Paradoxically, expression of mutant constitutively active Ras protein in primary human cells results in a premature proliferation arrest known as oncogene-induced senescence (OIS). This is more commonly observed in human pre-neoplasia than in neoplastic lesions, and is considered a tumor suppressor mechanism. Senescent cells are still metabolically active but in a status of cell cycle arrest characterized by specific morphological and physiological features that distinguish them from both proliferating cells, and cells growth-arrested by other means. Although the molecular mechanisms by which OIS is established are not totally understood, the current view is that OIS in human cells is tightly linked to persistent activation of the DNA damage response (DDR) pathway, as a consequence of replication stress. Here we will highlight recent advances in our understanding of molecular mechanisms leading to hyper-replication stress in response to oncogene activation, and of the crosstalk between replication stress and persistent activation of the DDR. We will also discuss new evidence for DNA repair deficiencies during OIS, which might increase the genomic instability that drives senescence bypass and malignant transformation.
Collapse
Affiliation(s)
- Simona Graziano
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA
| | - Susana Gonzalo
- Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
| |
Collapse
|
|
22
|
Leng C, Zhang ZG, Chen WX, Luo HP, Song J, Dong W, Zhu XR, Chen XP, Liang HF, Zhang BX. An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK-AKT pathway. Cancer Lett 2016; 376:188-196. [PMID: 26996299 DOI: 10.1016/j.canlet.2016.03.023] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 02/09/2016] [Accepted: 03/11/2016] [Indexed: 11/23/2022]
Abstract
Anoikis, a form of programmed cell death, occurs when the cells are detached from the appropriate extracellular matrix. Anoikis resistance or anchorage independence is necessary for distant metastases of cancer. The mechanisms by which hepatocellular carcinoma (HCC) cells become resistant to anoikis are not fully understood. Integrin beta4 (ITGB4, also known as CD104) is associated with progression of many human cancers. In this study, we demonstrate that ITGB4 is over-expressed in HCC tissues and aggressive HCC cell lines. To explore the role of ITGB4 in HCC, we inhibited its expression using small interfering RNA in two HCC cell lines: HCCLM3 and HLF. We show that knockdown of ITGB4 significantly enhanced susceptibility to anoikis through inhibition of AKT/PKB signaling. Moreover, ITGB4 interacts with epidermal growth factor receptor (EGFR) in a ligand independent manner. Inactivation of EGFR inhibits the anchorage independence and AKT pathway promoted by ITGB4. Further investigation proved that the ITGB4-EGFR unit triggers the focal adhesion kinase (FAK) to activate the AKT signaling pathway. Finally, we demonstrate that over-expression of ITGB4 is positively associated with tumor growth and lung metastases of HCC in vivo. Collectively, we demonstrate for the first time that ITGB4 is overexpressed in HCC tissues and promotes metastases of HCC by conferring anchorage independence through EGFR-dependent FAK-AKT activation.
Collapse
Affiliation(s)
- Chao Leng
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Zhan-Guo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Wei-Xun Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Hong-Ping Luo
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Jia Song
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Wei Dong
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Xuan-Ru Zhu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China
| | - Hui-Fang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China.
| | - Bi-Xiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China.
| |
Collapse
|
|
23
|
Goulielmaki M, Koustas E, Moysidou E, Vlassi M, Sasazuki T, Shirasawa S, Zografos G, Oikonomou E, Pintzas A. BRAF associated autophagy exploitation: BRAF and autophagy inhibitors synergise to efficiently overcome resistance of BRAF mutant colorectal cancer cells. Oncotarget 2016; 7:9188-9221. [PMID: 26802026 PMCID: PMC4891035 DOI: 10.18632/oncotarget.6942] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 01/02/2016] [Indexed: 02/05/2023] Open
Abstract
Autophagy is the basic catabolic mechanism that involves cell degradation of unnecessary or dysfunctional cellular components. Autophagy has a controversial role in cancer--both in protecting against tumor progression by isolation of damaged organelles, or by potentially contributing to cancer growth. The impact of autophagy in RAS induced transformation still remains to be further analyzed based on the differential effect of RAS isoforms and tumor cell context. In the present study, the effect of KRAS/BRAF/PIK3CA oncogenic pathways on the autophagic cell properties and on main components of the autophagic machinery like p62 (SQSTM1), Beclin-1 (BECN1) and MAP1LC3 (LC3) in colon cancer cells was investigated. This study provides evidence that BRAF oncogene induces the expression of key autophagic markers, like LC3 and BECN1 in colorectal tumor cells. Herein, PI3K/AKT/MTOR inhibitors induce autophagic tumor properties, whereas RAF/MEK/ERK signalling inhibitors reduce expression of autophagic markers. Based on the ineffectiveness of BRAFV600E inhibitors in BRAFV600E bearing colorectal tumors, the BRAF related autophagic properties in colorectal cancer cells are further exploited, by novel combinatorial anti-cancer protocols. Strong evidence is provided here that pre-treatment of autophagy inhibitor 3-MA followed by its combination with BRAFV600E targeting drug PLX4720 can synergistically sensitize resistant colorectal tumors. Notably, colorectal cancer cells are very sensitive to mono-treatments of another autophagy inhibitor, Bafilomycin A1. The findings of this study are expected to provide novel efficient protocols for treatment of otherwise resistant colorectal tumors bearing BRAFV600E, by exploiting the autophagic properties induced by BRAF oncogene.
Collapse
Affiliation(s)
- Maria Goulielmaki
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - Evangelos Koustas
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - Eirini Moysidou
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - Margarita Vlassi
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | | | - Senji Shirasawa
- Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - George Zografos
- 3rd Department of Surgery, General Hospital of Athens G. Gennimatas, Athens, Greece
| | - Eftychia Oikonomou
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| | - Alexander Pintzas
- Laboratory of Signal Mediated Gene Expression, Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece
| |
Collapse
|
|
24
|
Eng CH, Wang Z, Tkach D, Toral-Barza L, Ugwonali S, Liu S, Fitzgerald SL, George E, Frias E, Cochran N, De Jesus R, McAllister G, Hoffman GR, Bray K, Lemon L, Lucas J, Fantin VR, Abraham RT, Murphy LO, Nyfeler B. Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy. Proc Natl Acad Sci U S A 2016; 113:182-7. [PMID: 26677873 PMCID: PMC4711870 DOI: 10.1073/pnas.1515617113] [Citation(s) in RCA: 190] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition. By profiling 47 cell lines with pharmacological and genetic loss-of-function tools, we were unable to confirm that KRAS-driven tumor lines require macroautophagy for growth. Deletion of autophagy-related 7 (ATG7) by genome editing completely blocked macroautophagy in several tumor lines with oncogenic mutations in KRAS but did not inhibit cell proliferation in vitro or tumorigenesis in vivo. Furthermore, ATG7 knockout did not sensitize cells to irradiation or to several anticancer agents tested. Interestingly, ATG7-deficient and -proficient cells were equally sensitive to the antiproliferative effect of chloroquine, a lysosomotropic agent often used as a pharmacological tool to evaluate the response to macroautophagy inhibition. Moreover, both cell types manifested synergistic growth inhibition when treated with chloroquine plus the tyrosine kinase inhibitors erlotinib or sunitinib, suggesting that the antiproliferative effects of chloroquine are independent of its suppressive actions on autophagy.
Collapse
Affiliation(s)
| | - Zuncai Wang
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Diane Tkach
- Oncology Research Unit, Pfizer, Pearl River, NY 10965
| | | | - Savuth Ugwonali
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Shanming Liu
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Stephanie L Fitzgerald
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Elizabeth George
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Elizabeth Frias
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Nadire Cochran
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Rowena De Jesus
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Gregory McAllister
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Gregory R Hoffman
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Kevin Bray
- Oncology Research Unit, Pfizer, Pearl River, NY 10965
| | - LuAnna Lemon
- Oncology Research Unit, Pfizer, Pearl River, NY 10965
| | - Judy Lucas
- Oncology Research Unit, Pfizer, Pearl River, NY 10965
| | | | | | - Leon O Murphy
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, MA 02139
| | - Beat Nyfeler
- Department of Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, CH-4056 Basel, Switzerland
| |
Collapse
|
|
25
|
Jung YY, Lee YK, Koo JS. The potential of Beclin 1 as a therapeutic target for the treatment of breast cancer. Expert Opin Ther Targets 2015; 20:167-78. [PMID: 26357854 DOI: 10.1517/14728222.2016.1085971] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Beclin 1 plays a crucial role in autophagy via the Beclin 1 interactome, and is involved in various biological processes such as protein sorting, chemokinesis, and cell death. Via these biologic functions, Beclin 1 contributes to both tumor suppression and tumor progression. AREAS COVERED Beclin 1 plays a key biologic function on cell homeostasis and affects tumorigenesis. In this review, detailing up-to-date knowledge on the tumorigenic role of Beclin 1, its implication in breast cancer, and its utility as a breast cancer-specific drug target is discussed. EXPERT OPINION Because Beclin 1 is expressed in breast cancer cells, Beclin 1 could be a unique, effective drug target for the prevention and treatment of breast cancer. However, the expression of Beclin 1 varies according to cancer molecular subtypes, and Beclin 1 is involved in both breast cancer suppression and tumor progression; therefore, the decision of using a Beclin 1 inducer or inhibitor should be made based on breast cancer stage and subtype.
Collapse
Affiliation(s)
- Yoon Yang Jung
- a Yonsei University College of Medicine, Severance Hospital, Department of Pathology , 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea ;
| | - Yu Kyung Lee
- a Yonsei University College of Medicine, Severance Hospital, Department of Pathology , 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea ;
| | - Ja Seung Koo
- a Yonsei University College of Medicine, Severance Hospital, Department of Pathology , 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, South Korea ;
| |
Collapse
|
|
26
|
11'-Deoxyverticillin A (C42) promotes autophagy through K-Ras/GSK3 signaling pathway in HCT116 cells. Protein Cell 2015; 5:945-9. [PMID: 25261996 PMCID: PMC4259883 DOI: 10.1007/s13238-014-0099-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
|
|
27
|
Lin PY, Chang CD, Chen YC, Shih WL. RhoA/ROCK1 regulates Avian Reovirus S1133-induced switch from autophagy to apoptosis. BMC Vet Res 2015; 11:103. [PMID: 25944062 PMCID: PMC4430033 DOI: 10.1186/s12917-015-0417-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 04/26/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Autophagy is an essential process in the control of cellular homeostasis. It enables cells under certain stress conditions to survive by removing toxic cellular components, and may protect cells from apoptosis. In the present study, the signaling pathways involved in ARV S1133 regulated switch from autophagy to apoptosis were investigated. RESULTS ARV S1133 infection caused autophagy in the early to middle infectious stages in Vero and DF1 cells, and apoptosis in the middle to late stages. Conversion of the autophagy marker LC3-I to LC3-II occurred earlier than cleavage of the apoptotic marker caspase-3. ARV S1133 also activated the Beclin-1 promoter in the early to middle stages of infection. Levels of RhoA-GTP and ROCK1 activity were elevated upon ARV S1133 infection, while inhibition of RhoA and ROCK1 reduced autophagy and subsequent apoptosis. Conversely, inhibition of caspase-3 did not affect the level of autophagy. Beclin-1 knockdown and treatment with autophagy inhibitors, 3-MA and Bafilomycin A1, suppressed ARV S1133-induced autophagy and apoptosis simultaneously, suggesting the shift from autophagy to apoptosis. A co-immunoprecipitation assay demonstrated that the formation of a RhoA, ROCK1 and Beclin-1 complex coincided with the induction of autophagy. CONCLUSION Our results demonstrate that RhoA/ROCK1 signaling play critical roles in the transition of cell activity from autophagy to apoptosis in ARV S1133-infected cells.
Collapse
Affiliation(s)
- Ping-Yuan Lin
- Department of Biological Science and Technology, Pingtung, 91201, Taiwan.
| | - Ching-Dong Chang
- Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung, Taiwan.
| | - Yo-Chia Chen
- Department of Biological Science and Technology, Pingtung, 91201, Taiwan.
| | - Wen-Ling Shih
- Department of Biological Science and Technology, Pingtung, 91201, Taiwan. .,Graduate Institute of Biotechnology, National Pingtung University of Science and Technology, 1, Shuefu Rd., Neipu, Pingtung, 91201, Taiwan.
| |
Collapse
|
|
28
|
Abstract
Autophagy, a process of self-degradation and turnover of cellular components, plays a complex role in cancer. Evidence exists to show that autophagy may support tumor growth and cell survival, whereas it can also contribute to tumor suppression and have anti-survival characteristics in different cellular systems. Numerous studies have described the effects of various oncogenes and tumor suppressors on autophagy. The small GTPase Ras is an oncogene involved in the regulation of various cell-signaling pathways, and is mutated in 33% of human cancers. In the present review, we discuss the interplay between Ras and autophagy in relation to oncogenesis. It appears that Ras can upregulate or downregulate autophagy through several signaling pathways. In turn, autophagy can affect the tumorigenicity driven by Ras, resulting in either tumor progression or repression, depending on the cellular context. Furthermore, Ras inhibitors were shown to induce autophagy in several cancer cell lines.
Collapse
Affiliation(s)
- Eran Schmukler
- Department of Neurobiology. Tel-Aviv University, Ramat-Aviv, Israel
| | | | | |
Collapse
|
|
29
|
Yoo BH, Zagryazhskaya A, Li Y, Koomson A, Khan IA, Sasazuki T, Shirasawa S, Rosen KV. Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy-independent apoptosis of the attached cells. Autophagy 2015; 11:1230-46. [PMID: 26061804 PMCID: PMC4590629 DOI: 10.1080/15548627.2015.1056968] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Revised: 05/11/2015] [Accepted: 05/22/2015] [Indexed: 01/20/2023] Open
Abstract
Detachment of nonmalignant intestinal epithelial cells from the extracellular matrix (ECM) triggers their growth arrest and, ultimately, apoptosis. In contrast, colorectal cancer cells can grow without attachment to the ECM. This ability is critical for their malignant potential. We found previously that detachment-induced growth arrest of nonmalignant intestinal epithelial cells is driven by their detachment-triggered autophagy, and that RAS, a major oncogene, promotes growth of detached cells by blocking such autophagy. In an effort to identify the mechanisms of detachment-induced autophagy and growth arrest of nonmalignant cells we found here that detachment of these cells causes upregulation of ATG3 and that ATG3 upregulation contributes to autophagy and growth arrest of detached cells. We also observed that when ATG3 expression is artificially increased in the attached cells, ATG3 promotes neither autophagy nor growth arrest but triggers their apoptosis. ATG3 upregulation likely promotes autophagy of the detached but not that of the attached cells because detachment-dependent autophagy requires other detachment-induced events, such as the upregulation of ATG7. We further observed that those few adherent cells that do not die by apoptosis induced by ATG3 become resistant to apoptosis caused by cell detachment, a property that is critical for the ability of normal epithelial cells to become malignant. We conclude that cell-ECM adhesion can switch ATG3 functions: when upregulated in detached cells in the context of other autophagy-promoting events, ATG3 contributes to autophagy. However, when overexpressed in the adherent cells, in the circumstances not favoring autophagy, ATG3 triggers apoptosis.
Collapse
Affiliation(s)
- Byong Hoon Yoo
- Departments of Pediatrics & Biochemistry and Molecular Biology; Dalhousie University; Halifax, NS Canada
| | - Anna Zagryazhskaya
- Departments of Pediatrics & Biochemistry and Molecular Biology; Dalhousie University; Halifax, NS Canada
| | - Yongling Li
- Departments of Pediatrics & Biochemistry and Molecular Biology; Dalhousie University; Halifax, NS Canada
| | - Ananda Koomson
- Departments of Pediatrics & Biochemistry and Molecular Biology; Dalhousie University; Halifax, NS Canada
| | - Iman Aftab Khan
- Departments of Pediatrics & Biochemistry and Molecular Biology; Dalhousie University; Halifax, NS Canada
| | | | - Senji Shirasawa
- Department of Cell Biology; Faculty of Medicine & Center for Advanced Molecular Medicine; Fukuoka University; Fukuoka, Japan
| | - Kirill V Rosen
- Departments of Pediatrics & Biochemistry and Molecular Biology; Dalhousie University; Halifax, NS Canada
| |
Collapse
|
|
30
|
Schmukler E, Wolfson E, Haklai R, Elad-Sfadia G, Kloog Y, Pinkas-Kramarski R. Chloroquine synergizes with FTS to enhance cell growth inhibition and cell death. Oncotarget 2014; 5:173-84. [PMID: 24368422 PMCID: PMC3960199 DOI: 10.18632/oncotarget.1500] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
The Ras family of small GTPases transmits extracellular signals that regulate cell growth, differentiation, motility and death. Ras signaling is constitutively active in a large number of human cancers. Ras can also regulate autophagy by affecting several signaling pathways including the mTOR pathway. Autophagy is a process that regulates the balance between protein synthesis and protein degradation. It is important for normal growth control, but may be defective in diseases. Previously, we have shown that Ras inhibition by FTS induces autophagy, which partially protects cancer cells and may limit the use of FTS as an anti-cancer drug. Since FTS is a non toxic drug we hypothesized that FTS and chloroquine (an autophagy inhibitor) will synergize in cell growth inhibition and cell death. Thus, in the present study, we explored the mechanism of each individual drug and their combined action. Our results demonstrate that in HCT-116 and in Panc-1 cells, FTS induces autophagy, which can be inhibited by chloroquine. Furthermore, the combined treatment synergistically decreased the number of viable cells. Interestingly, the combined treatment enhanced apoptotic cell death as indicated by increased sub-G1 cell population, increased Hoechst staining, activation of caspase 3, decrease in survivin expression and release of cytochrome c. Thus, chloroquine treatment may promote FTS-mediated inhibition of tumor cell growth and may stimulate apoptotic cell death.
Collapse
Affiliation(s)
- Eran Schmukler
- Department of Neurobiology. Tel-Aviv University, Ramat-Aviv, Israel
| | | | | | | | | | | |
Collapse
|
|
31
|
Titone R, Morani F, Follo C, Vidoni C, Mezzanzanica D, Isidoro C. Epigenetic control of autophagy by microRNAs in ovarian cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:343542. [PMID: 24877083 PMCID: PMC4022060 DOI: 10.1155/2014/343542] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Accepted: 04/14/2014] [Indexed: 12/22/2022]
Abstract
Autophagy is a lysosomal-driven catabolic process that contributes to the preservation of cell homeostasis through the regular elimination of cellular damaged, aged, and redundant molecules and organelles. Autophagy plays dual opposite roles in cancer: on one hand it prevents carcinogenesis; on the other hand it confers an advantage to cancer cells to survive under prohibitive conditions. Autophagy has been implicated in ovarian cancer aggressiveness and in ovarian cancer cell chemoresistance and dormancy. Small noncoding microRNAs (miRNAs) regulate gene expression at posttranscriptional level, thus playing an important role in many aspects of cell pathophysiology, including cancerogenesis and cancer progression. Certain miRNAs have recently emerged as important epigenetic modulators of autophagy in cancer cells. The mRNA of several autophagy-related genes contains, in fact, the target sequence for miRNAs belonging to different families, with either oncosuppressive or oncogenic activities. MiRNA profiling studies have identified some miRNAs aberrantly expressed in ovarian cancer tissues that can impact autophagy. In addition, plasma and stroma cell-derived miRNAs in tumour-bearing patients can regulate the expression of relevant autophagy genes in cancer cells. The present review focuses on the potential implications of miRNAs regulating autophagy in ovarian cancer pathogenesis and progression.
Collapse
Affiliation(s)
- Rossella Titone
- Laboratory of Molecular Pathology, Department of Health Sciences, Centro di Biotecnologie per la Ricerca Medica Applicata, Università del Piemonte Orientale, Via P. Solaroli 17, 28100 Novara, Italy
| | - Federica Morani
- Laboratory of Molecular Pathology, Department of Health Sciences, Centro di Biotecnologie per la Ricerca Medica Applicata, Università del Piemonte Orientale, Via P. Solaroli 17, 28100 Novara, Italy
| | - Carlo Follo
- Laboratory of Molecular Pathology, Department of Health Sciences, Centro di Biotecnologie per la Ricerca Medica Applicata, Università del Piemonte Orientale, Via P. Solaroli 17, 28100 Novara, Italy
| | - Chiara Vidoni
- Laboratory of Molecular Pathology, Department of Health Sciences, Centro di Biotecnologie per la Ricerca Medica Applicata, Università del Piemonte Orientale, Via P. Solaroli 17, 28100 Novara, Italy
| | - Delia Mezzanzanica
- Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
| | - Ciro Isidoro
- Laboratory of Molecular Pathology, Department of Health Sciences, Centro di Biotecnologie per la Ricerca Medica Applicata, Università del Piemonte Orientale, Via P. Solaroli 17, 28100 Novara, Italy
| |
Collapse
|
|
32
|
Belaid A, Ndiaye PD, Cerezo M, Cailleteau L, Brest P, Klionsky DJ, Carle GF, Hofman P, Mograbi B. Autophagy and SQSTM1 on the RHOA(d) again: emerging roles of autophagy in the degradation of signaling proteins. Autophagy 2013; 10:201-8. [PMID: 24300375 DOI: 10.4161/auto.27198] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Degradation of signaling proteins is one of the most powerful tumor-suppressive mechanisms by which a cell can control its own growth, its survival, and its motility. Emerging evidence suggests that autophagy limits several signaling pathways by degrading kinases, downstream components, and transcription factors; however, this often occurs under stressful conditions. Our recent studies revealed that constitutive autophagy temporally and spatially controls the RHOA pathway. Specifically, inhibition of autophagosome degradation induces the accumulation of the GTP-bound form of RHOA. The active RHOA is sequestered via SQSTM1/p62 within autolysosomes, and accordingly fails to localize to the spindle midbody or to the cell surface, as we demonstrate herein. As a result, all RHOA-downstream responses are deregulated, thus driving cytokinesis failure, aneuploidy and motility, three processes that directly have an impact upon cancer progression. We therefore propose that autophagy acts as a degradative brake for RHOA signaling and thereby controls cell proliferation, migration, and genome stability.
Collapse
Affiliation(s)
- Amine Belaid
- Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Equipe Labellisée par l'ARC; Villejuif, France; Centre Antoine Lacassagne; Nice, France
| | - Papa Diogop Ndiaye
- Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Equipe Labellisée par l'ARC; Villejuif, France; Centre Antoine Lacassagne; Nice, France
| | - Michaël Cerezo
- Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; INSERM U895/C3M: Centre Méditerranéen de Médecine Moléculaire; Nice, France
| | - Laurence Cailleteau
- Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France
| | - Patrick Brest
- Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Equipe Labellisée par l'ARC; Villejuif, France; Centre Antoine Lacassagne; Nice, France
| | | | - Georges F Carle
- Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Centre Antoine Lacassagne; Nice, France; Laboratoire TIRO-MATOs UMR E4320; Commissariat à l'Energie Atomique; Nice, France
| | - Paul Hofman
- Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Equipe Labellisée par l'ARC; Villejuif, France; Centre Antoine Lacassagne; Nice, France; Centre Hospitalier Universitaire de Nice; Pasteur Hospital; Laboratory of Clinical and Experimental Pathology; Nice, France
| | - Baharia Mograbi
- Institute of Research on Cancer and Ageing of Nice (IRCAN); INSERM U1081; CNRS UMR7284; Nice, France; Université de Nice-Sophia Antipolis; Faculté de Médecine; Nice, France; Equipe Labellisée par l'ARC; Villejuif, France; Centre Antoine Lacassagne; Nice, France
| |
Collapse
|
|
33
|
The interplay between epigenetic silencing, oncogenic KRas and HIF-1 regulatory pathways in control of BNIP3 expression in human colorectal cancer cells. Biochem Biophys Res Commun 2013; 441:707-12. [PMID: 24211581 DOI: 10.1016/j.bbrc.2013.10.098] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 10/18/2013] [Indexed: 01/22/2023]
Abstract
Bcl-2/adenovirus E1B-19kDa-interacting protein 3 (BNIP3) is an important mediator of cell survival and a member of the Bcl-2 family of proteins that regulate programmed cell death and autophagy. We have previously established a link between the expression of oncogenic HRas and up-regulation of BNIP3 and the control of autophagy in cancer cells. However, in view of varied expression of BNIP3 in different tumor types and emerging uncertainties as to the role of epigenetic silencing, oncogenic regulation and the role of BNIP3 in cancer are still poorly understood. In the present study we describe profound effect of KRas on the expression of methylated BNIP3 in colorectal cancer cells and explore the interplay between HIF-1, hypoxia pathway and oncogenic KRas in this context. We observed that BNIP3 mRNA remains undetectable in aggressive DLD-1 cells harboring G13D mutant KRAS and HT-29 colorectal cancer cells unless the cells are exposed to demethylating agents such as 5-aza-2'-deoxycytidine. Following this treatment BNIP3 expression remains uniquely dependent on the Ras activity. We found that hypoxia or pharmacological activation of HIF-1 alone contributes to, but is not sufficient for efficient induction of BNIP3 mRNA transcription in cells lacking mutant KRas activity. The up-regulation of BNIP3 by KRas in this setting is mediated by the MAPK pathway, and is attenuated by the respective inhibitors (PD98059, U0126). Thus, we demonstrate the novel mechanism where activity of Ras is essential for 5-aza-2'-deoxycytidine-mediated BNIP3 expression. Moreover, we found that 5-aza-2'-deoxycytidine-mediated or enforced up-regulation of BNIP3 in DLD-1 cells results in KRas-dependent resistance to 5-Fluorouracil.
Collapse
|
|
34
|
Yang J, Zheng Z, Yan X, Li X, Liu Z, Ma Z. Integration of autophagy and anoikis resistance in solid tumors. Anat Rec (Hoboken) 2013; 296:1501-8. [PMID: 23963853 DOI: 10.1002/ar.22769] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 06/16/2013] [Indexed: 12/27/2022]
Abstract
Macroautophagy or autophagy is a lysosome-dependent process in which enzymatic degradation and recycling of cytosolic components occurred due to stressful conditions. This cellular arrangement imparts anoikis resistance in solid tumors. Anoikis, a special form of apoptosis occurring when cells detach from the extracellular matrix, is a critical mechanism in maintaining tissue homeostasis and development. Anoikis resistance facilitates tumorigenesis and metastasis. However, the complexity of the role of autophagy in tumor is underscored by evidence that autophagy can function as both a pro-survival or pro-death depending on the context and the stimuli, which are likely exploitable for tumor therapy. This review focuses on recent progress in understanding anoikis resistance and autophagy signaling, paying particular attention to its relevance in solid tumor metastasis.
Collapse
Affiliation(s)
- Jie Yang
- Department of Biochemistry and Molecular Biology, Heping District, Tianjin, 300070, China
| | | | | | | | | | | |
Collapse
|
|
35
|
Zheng Z, Yang J, Zhao D, Gao D, Yan X, Yao Z, Liu Z, Ma Z. Downregulated adaptor protein p66(Shc) mitigates autophagy process by low nutrient and enhances apoptotic resistance in human lung adenocarcinoma A549 cells. FEBS J 2013; 280:4522-30. [PMID: 23815759 DOI: 10.1111/febs.12416] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2013] [Revised: 04/11/2013] [Accepted: 06/25/2013] [Indexed: 12/31/2022]
Abstract
Macroautophagy or autophagy is a lysosome-dependent process in which enzymatic degradation and recycling of cytosolic components occur in stressful contexts. The mechanisms underlying the signaling from starvation to the regulation of autophagy are not fully understood. We previously showed that the Src family member p66(Shc) (focal adhesion-associated 66 kDa isoform of the Src homology and collagen) promotes anoikis and suppresses tumor metastasis via k-Ras-dependent control of proliferation and survival. However, the role of p66(Shc) in low-nutrient-induced autophagy-related pathways remains elusive. In this work, human lung adenocarcinoma A549 cells were used to further investigate the biological effects of p66(Shc) on autophagy and apoptotic resistance. Here, we show that deficiency of p66(Shc) mitigates the low-nutrient-induced autophagy process in the levels of microtubule-associated protein 1A light chain protein 3B (LC3B) conversion, in the number of autophagic vacuoles and in p62/sequestosome 1 protein degradation. However, autophagy-related protein Beclin 1 was not significantly changed during low-nutrient treatment. Furthermore, we found that prolonged phosphorylation of extracellular signaling-regulated kinase (Erk)1/2, but not phosphorylation of Akt is significantly sustained when p66(Shc) expression is inhibited by shRNA. In addition, cleavage of caspase 7 and poly(ADP-ribose) polymerase, but not caspase 6 and 9 are retarded with this effect compared to the shRNA control cells. Together, these findings suggest the possibility that p66(Shc) plays a pivotal role in coordinately regulating autophagy process and apoptotic resistance in A549 cells under nutrient-limited conditions.
Collapse
Affiliation(s)
- Zhichao Zheng
- Tianjin Key Laboratory of Medical Epigenetics, Tianjin Medical University, China
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Bellot GL, Liu D, Pervaiz S. ROS, autophagy, mitochondria and cancer: Ras, the hidden master? Mitochondrion 2013; 13:155-62. [DOI: 10.1016/j.mito.2012.06.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Accepted: 06/22/2012] [Indexed: 12/31/2022]
|
|
37
|
Del Bello B, Toscano M, Moretti D, Maellaro E. Cisplatin-induced apoptosis inhibits autophagy, which acts as a pro-survival mechanism in human melanoma cells. PLoS One 2013; 8:e57236. [PMID: 23437349 PMCID: PMC3577730 DOI: 10.1371/journal.pone.0057236] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2012] [Accepted: 01/18/2013] [Indexed: 01/11/2023] Open
Abstract
The interplay between a non-lethal autophagic response and apoptotic cell death is still a matter of debate in cancer cell biology. In the present study performed on human melanoma cells, we investigate the role of basal or stimulated autophagy in cisplatin-induced cytotoxicity, as well as the contribution of cisplatin-induced activation of caspases 3/7 and conventional calpains. The results show that, while down-regulating Beclin-1, Atg14 and LC3-II, cisplatin treatment inhibits the basal autophagic response, impairing a physiological pro-survival response. Consistently, exogenously stimulated autophagy, obtained with trehalose or calpains inhibitors (MDL-28170 and calpeptin), protects from cisplatin-induced apoptosis, and such a protection is reverted by inhibiting autophagy with 3-methyladenine or ATG5 silencing. In addition, during trehalose-stimulated autophagy, the cisplatin-induced activation of calpains is abrogated, suggesting the existence of a feedback loop between the autophagic process and calpains. On the whole, our results demonstrate that in human melanoma cells autophagy may function as a beneficial stress response, hindered by cisplatin-induced death mechanisms. In a therapeutic perspective, these findings suggest that the efficacy of cisplatin-based polychemotherapies for melanoma could be potentiated by inhibitors of autophagy.
Collapse
Affiliation(s)
- Barbara Del Bello
- Department of Pathophysiology, Experimental Medicine and Public Health, Istituto Toscano Tumori, University of Siena, Siena, Italy
| | - Marzia Toscano
- Department of Pathophysiology, Experimental Medicine and Public Health, Istituto Toscano Tumori, University of Siena, Siena, Italy
| | - Daniele Moretti
- Department of Pathophysiology, Experimental Medicine and Public Health, Istituto Toscano Tumori, University of Siena, Siena, Italy
| | - Emilia Maellaro
- Department of Pathophysiology, Experimental Medicine and Public Health, Istituto Toscano Tumori, University of Siena, Siena, Italy
- * E-mail:
| |
Collapse
|
|
38
|
Autophagic activity dictates the cellular response to oncogenic RAS. Proc Natl Acad Sci U S A 2012; 109:13325-30. [PMID: 22847423 DOI: 10.1073/pnas.1120193109] [Citation(s) in RCA: 90] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
RAS is frequently mutated in human cancers and has opposing effects on autophagy and tumorigenesis. Identifying determinants of the cellular responses to RAS is therefore vital in cancer research. Here, we show that autophagic activity dictates the cellular response to oncogenic RAS. N-terminal Apoptosis-stimulating of p53 protein 2 (ASPP2) mediates RAS-induced senescence and inhibits autophagy. Oncogenic RAS-expressing ASPP2((Δ3/Δ3)) mouse embryonic fibroblasts that escape senescence express a high level of ATG5/ATG12. Consistent with the notion that autophagy levels control the cellular response to oncogenic RAS, overexpressing ATG5, but not autophagy-deficient ATG5 mutant K130R, bypasses RAS-induced senescence, whereas ATG5 or ATG3 deficiency predisposes to it. Mechanistically, ASPP2 inhibits RAS-induced autophagy by competing with ATG16 to bind ATG5/ATG12 and preventing ATG16/ATG5/ATG12 formation. Hence, ASPP2 modulates oncogenic RAS-induced autophagic activity to dictate the cellular response to RAS: to proliferate or senesce.
Collapse
|
|
39
|
Regulation of autophagy by glucose in Mammalian cells. Cells 2012; 1:372-95. [PMID: 24710481 PMCID: PMC3901114 DOI: 10.3390/cells1030372] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2012] [Revised: 06/22/2012] [Accepted: 07/13/2012] [Indexed: 02/07/2023] Open
Abstract
Autophagy is an evolutionarily conserved process that contributes to maintain cell homeostasis. Although it is strongly regulated by many extracellular factors, induction of autophagy is mainly produced by starvation of nutrients. In mammalian cells, the regulation of autophagy by amino acids, and also by the hormone insulin, has been extensively investigated, but knowledge about the effects of other autophagy regulators, including another nutrient, glucose, is more limited. Here we will focus on the signalling pathways by which environmental glucose directly, i.e., independently of insulin and glucagon, regulates autophagy in mammalian cells, but we will also briefly mention some data in yeast. Although glucose deprivation mainly induces autophagy via AMPK activation and the subsequent inhibition of mTORC1, we will also comment other signalling pathways, as well as evidences indicating that, under certain conditions, autophagy can be activated by glucose. A better understanding on how glucose regulates autophagy not only will expand our basic knowledge of this important cell process, but it will be also relevant to understand common human disorders, such as cancer and diabetes, in which glucose levels play an important role.
Collapse
|
|
40
|
Cheng Y, Sk UH, Zhang Y, Ren X, Zhang L, Huber-Keener KJ, Sun YW, Liao J, Amin S, Sharma AK, Yang JM. Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death. PLoS One 2012; 7:e35104. [PMID: 22496897 PMCID: PMC3320619 DOI: 10.1371/journal.pone.0035104] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2011] [Accepted: 03/08/2012] [Indexed: 01/23/2023] Open
Abstract
Background The DNA alkylating agent temozolomide (TMZ) is widely used in the treatment of human malignancies such as glioma and melanoma. On the basis of previous structure-activity studies, we recently synthesized a new TMZ selenium analog by rationally introducing an N-ethylselenocyanate extension to the amide functionality in TMZ structure. Principal Findings This TMZ-Se analog showed a superior cytotoxicity to TMZ in human glioma and melanoma cells and a more potent tumor-inhibiting activity than TMZ in mouse glioma and melanoma xenograft model. TMZ-Se was also effective against a TMZ-resistant glioma cell line. To explore the mechanism underlying the superior antitumor activity of TMZ-Se, we compared the effects of TMZ and TMZ-Se on apoptosis and autophagy. Apoptosis was significantly increased in tumor cells treated with TMZ-Se in comparison to those treated with TMZ. TMZ-Se also triggered greater autophagic response, as compared with TMZ, and suppressing autophagy partly rescued cell death induced by TMZ-Se, indicating that TMZ-Se-triggered autophagy contributed to cell death. Although mRNA level of the key autophagy gene, Beclin 1, was increased, Beclin 1 protein was down-regulated in the cells treated with TMZ-Se. The decrease in Beclin 1 following TMZ-Se treatment were rescued by the calpain inhibitors and the calpain-mediated degradation of Beclin1 had no effect on autophagy but promoted apoptosis in cells treated with TMZ-Se. Conclusions Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug.
Collapse
Affiliation(s)
- Yan Cheng
- Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, Pennsylvania, United States of America
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Changes in beclin-1 and micro-calpain expression in tri-ortho-cresyl phosphate-induced delayed neuropathy. Toxicol Lett 2012; 210:276-84. [PMID: 22366639 DOI: 10.1016/j.toxlet.2012.02.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 02/10/2012] [Accepted: 02/13/2012] [Indexed: 11/23/2022]
Abstract
Tri-ortho-cresyl phosphate (TOCP) can cause toxic neuropathy known as organophosphate-induced delayed neuropathy (OPIDN), which is pathologically characterized by the swollen axon containing aggregations of neurofilaments, microtubules, and multivesicular vesicles. Autophagy is a self-degradative process which plays a housekeeping role in removing misfolded proteins and damaged organelles. The current study was designed to investigate the possible roles of autophagy in the pathogenesis of OPIDN. Adult hens were treated with a dose of 750mg/kg TOCP by gavage, or injected subcutaneously with 60mg/kg phenylmethanesulfonyl fluoride (PMSF) dissolved in DMSO 24h earlier and subsequently treated with TOCP, then sacrificed on the time-points of 0, 1, 5, 10, and 21 days after dosing of TOCP respectively. The levels of beclin-1 and μ-calpain in tibial nerves and spinal cords were determined by immunoblotting. The results showed that in both tissues TOCP increased the expression of μ-calpain while decreased that of beclin-1. When given before TOCP administration, PMSF pretreatment could protect hens against the delayed neuropathy. In the meantime, pretreatment with PMSF reduced calpain expression below basal and increased beclin-1 expression above basal in tibial nerve, whereas it simply returned calpain and beclin-1 expression to their basal levels in spinal cord. In conclusion, the intoxication of TOCP was associated with a significant change of beclin-1 in hen nervous tissues, which suggested that disruption of autophagy-regulated machinery in neurons might be involved in the pathogenesis of OPIDN.
Collapse
|
|
42
|
Abstract
Autophagy is a lysosomal degradation pathway that degrades damaged or superfluous cell components into basic biomolecules, which are then recycled back into the cytosol. In this respect, autophagy drives a flow of biomolecules in a continuous degradation-regeneration cycle. Autophagy is generally considered a pro-survival mechanism protecting cells under stress or poor nutrient conditions. Current research clearly shows that autophagy fulfills numerous functions in vital biological processes. It is implicated in development, differentiation, innate and adaptive immunity, ageing and cell death. In addition, accumulating evidence demonstrates interesting links between autophagy and several human diseases and tumor development. Therefore, autophagy seems to be an important player in the life and death of cells and organisms. Despite the mounting knowledge about autophagy, the mechanisms through which the autophagic machinery regulates these diverse processes are not entirely understood. In this review, we give a comprehensive overview of the autophagic signaling pathway, its role in general cellular processes and its connection to cell death. In addition, we present a brief overview of the possible contribution of defective autophagic signaling to disease.
Collapse
Affiliation(s)
- Ellen Wirawan
- VIB, Department for Molecular Biomedical Research, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium
- Department of Biomedical Molecular Biology, Unit for Molecular Signaling and Cell Death, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium
| | - Tom Vanden Berghe
- VIB, Department for Molecular Biomedical Research, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium
- Department of Biomedical Molecular Biology, Unit for Molecular Signaling and Cell Death, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium
| | - Saskia Lippens
- VIB, Department for Molecular Biomedical Research, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium
- Department of Biomedical Molecular Biology, Unit for Molecular Signaling and Cell Death, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium
| | - Patrizia Agostinis
- KULeuven, Laboratory for Cell Death and Therapy, Department for Molecular and Cell Biology, O&N I Herestraat 49, B-3000 Leuven, Belgium
| | - Peter Vandenabeele
- VIB, Department for Molecular Biomedical Research, Unit for Molecular Signaling and Cell Death, Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium
- Department of Biomedical Molecular Biology, Unit for Molecular Signaling and Cell Death, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium
| |
Collapse
|
|
43
|
Hoare M, Young ARJ, Narita M. Autophagy in cancer: having your cake and eating it. Semin Cancer Biol 2011; 21:397-404. [PMID: 21945348 DOI: 10.1016/j.semcancer.2011.09.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 09/07/2011] [Indexed: 12/24/2022]
Abstract
Autophagy, one of two major intracellular degradation pathways, plays a critical role in energy homeostasis and the quality control of macromolecules and intracellular organelles. Previous work has demonstrated the importance of autophagy in maintaining cellular fitness, both in healthy and stressful conditions, revealing the complex interplay between autophagy and other stress-responsive phenotypes. The complex outcomes of stress-responsive autophagy confer on it both pro- and anti-tumourigenic roles, depending on the cellular and environmental context. Furthermore, recent findings that functionally link autophagy to the tumour suppressor mechanism, cellular senescence, have revealed a new role of autophagy in cancer biology. In this review we summarise the current evidence on the relationship between autophagy and cancer, with a focus on its role in senescence.
Collapse
Affiliation(s)
- Matthew Hoare
- Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
| | | | | |
Collapse
|
|
44
|
Yoo BH, Wang Y, Erdogan M, Sasazuki T, Shirasawa S, Corcos L, Sabapathy K, Rosen KV. Oncogenic ras-induced down-regulation of pro-apoptotic protease caspase-2 is required for malignant transformation of intestinal epithelial cells. J Biol Chem 2011; 286:38894-903. [PMID: 21903589 DOI: 10.1074/jbc.m111.290692] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Resistance of carcinoma cells to anoikis, apoptosis that is normally induced by loss of cell-to-extracellular matrix adhesion, is thought to be essential for the ability of these cells to form primary tumors, invade adjacent tissues, and metastasize to distant organs. Current knowledge about the mechanisms by which cancer cells evade anoikis is far from complete. In an effort to understand these mechanisms, we found that ras, a major oncogene, down-regulates protease caspase-2 (which initiates certain steps of the cellular apoptotic program) in malignant human and rat intestinal epithelial cells. This down-regulation could be reversed by inhibition of a protein kinase Mek, a mediator of Ras signaling. We also found that enforced down-regulation of caspase-2 in nonmalignant intestinal epithelial cells by RNA interference protected them from anoikis. Furthermore, the reversal of the effect of Ras on caspase-2 achieved by the expression of exogenous caspase-2 in detached ras-transformed intestinal epithelial cells promoted well established apoptotic events, such as the release of the pro-apoptotic mitochondrial factors cytochrome c and HtrA2/Omi into the cytoplasm of these cells, significantly enhanced their anoikis susceptibility, and blocked their long term growth in the absence of adhesion to the extracellular matrix. Finally, the blockade of the effect of Ras on caspase-2 substantially suppressed growth of tumors formed by the ras-transformed cells in mice. We conclude that ras-induced down-regulation of caspase-2 represents a novel mechanism by which oncogenic Ras protects malignant intestinal epithelial cells from anoikis, promotes their anchorage-independent growth, and allows them to form tumors in vivo.
Collapse
Affiliation(s)
- Byong Hoon Yoo
- Department of Pediatrics, Atlantic Research Centre, Dalhousie University, Halifax, Nova Scotia B3H 4H7, Canada
| | | | | | | | | | | | | | | |
Collapse
|
|
45
|
Notte A, Leclere L, Michiels C. Autophagy as a mediator of chemotherapy-induced cell death in cancer. Biochem Pharmacol 2011; 82:427-34. [PMID: 21704023 DOI: 10.1016/j.bcp.2011.06.015] [Citation(s) in RCA: 140] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2011] [Revised: 06/08/2011] [Accepted: 06/08/2011] [Indexed: 12/15/2022]
Abstract
Since the 1940s, chemotherapy has been the treatment of choice for metastatic disease. Chemotherapeutic agents target proliferating cells, inducing cell death. For most of the history of chemotherapy, apoptosis was thought to be the only mechanism of drug-induced cell death. More recently, a second type of cell death pathway has emerged: autophagy, also called type II programmed cell death. Autophagy is a tightly regulated process by which selected components of a cell are degraded. It primarily functions as a cell survival adaptive mechanism during stress conditions. However, persistent stress can also promote extensive autophagy, leading to cell death, hence its name. Alterations in the autophagy pathway have been described in cancer cells that suggest a tumor-suppressive function in early tumorigenesis, but a tumor-promoting function in established tumors. Moreover, accumulating data indicate a role for autophagy in chemotherapy-induced cancer cell death. Here, we discuss some of the evidence showing autophagy-dependent cell death induced by anti-neoplastic agents in different cancer models. On the other hand, in some other examples, autophagy dampens treatment efficacy, hence providing a therapeutic target to enhance cancer cell killing. In this paper, we propose a putative mechanism that could reconcile these two opposite observations.
Collapse
Affiliation(s)
- Annick Notte
- URBC-NARILIS, University of Namur-FUNDP, 61 rue de Bruxelles, Namur, Belgium
| | | | | |
Collapse
|
|
46
|
Kaminskyy V, Zhivotovsky B. Proteases in autophagy. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2011; 1824:44-50. [PMID: 21640203 DOI: 10.1016/j.bbapap.2011.05.013] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2011] [Revised: 05/13/2011] [Accepted: 05/16/2011] [Indexed: 02/07/2023]
Abstract
Autophagy is a process involved in the proteolytic degradation of cellular macromolecules in lysosomes, which requires the activity of proteases, enzymes that hydrolyse peptide bonds and play a critical role in the initiation and execution of autophagy. Importantly, proteases also inhibit autophagy in certain cases. The initial steps of macroautophagy depend on the proteolytic processing of a particular protein, Atg8, by a cysteine protease, Atg4. This processing step is essential for conjugation of Atg8 with phosphatidylethanolamine and, subsequently, autophagosome formation. Lysosomal hydrolases, known as cathepsins, can be divided into several groups based on the catalitic residue in the active site, namely, cysteine, serine and aspartic cathepsins, which catalyse the cleavage of peptide bonds of autophagy substrates and, together with other factors, dispose of the autophagic flux. Whilst most cathepsins degrade autophagosomal content, some, such as cathepsin L, also degrade lysosomal membrane components, GABARAP-II and LC3-II. In contrast, cathepsin A, a serine protease, is involved in inhibition of chaperon-mediated autophagy through proteolytic processing of LAMP-2A. In addition, other families of calcium-dependent non-lysosomal cysteine proteases, such as calpains, and cysteine aspartate-specific proteases, such as caspases, may cleave autophagy-related proteins, negatively influencing the execution of autophagic processes. Here we discuss the current state of knowledge concerning protein degradation by autophagy and outline the role of proteases in autophagic processes. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
Collapse
Affiliation(s)
- Vitaliy Kaminskyy
- Institute of Environmental Medicine, Division of Toxicology, Karolinska Instituet, Stockholm, Sweden
| | | |
Collapse
|
|
47
|
Trocoli A, Djavaheri-Mergny M. The complex interplay between autophagy and NF-κB signaling pathways in cancer cells. Am J Cancer Res 2011; 1:629-649. [PMID: 21994903 PMCID: PMC3189824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2011] [Accepted: 04/22/2011] [Indexed: 05/31/2023] Open
Abstract
Tight regulation of both the NF-κB pathway and the autophagy process is necessary for maintenance of cellular homeostasis. Deregulation of both pathways is frequently observed in cancer cells and is associated with tumorigenesis and tumor cell resistance to cancer therapies. Autophagy is involved in several cellular functions regulated by NF-κB including cell survival, differentiation, senescence, inflammation, and immunity. On a molecular level, autophagy and NF-κB share common upstream signals and regulators and can control each other through positive or negative feedback loops, thus ensuring homeostatic responses. Here, we summarize and discuss the most recent discoveries that shed new light on the complex interplay between autophagy and NF-κB signaling pathways; this certainly has functional relevance in tumorigenesis and tumor responses to therapy.
Collapse
Affiliation(s)
- Aurore Trocoli
- NSERM U916 VINCO, Institut Bergonié229, cours de l'Argonne, 33076 Bordeaux Cedex France
- Université Bordeaux Ségalen146 rue Léo-Saignat, F-33076 Bordeaux cedex, France
| | - Mojgan Djavaheri-Mergny
- NSERM U916 VINCO, Institut Bergonié229, cours de l'Argonne, 33076 Bordeaux Cedex France
- Université Bordeaux Ségalen146 rue Léo-Saignat, F-33076 Bordeaux cedex, France
| |
Collapse
|
|
48
|
Kim MJ, Woo SJ, Yoon CH, Lee JS, An S, Choi YH, Hwang SG, Yoon G, Lee SJ. Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem 2011; 286:12924-32. [PMID: 21300795 PMCID: PMC3075639 DOI: 10.1074/jbc.m110.138958] [Citation(s) in RCA: 171] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2010] [Revised: 01/11/2011] [Indexed: 12/13/2022] Open
Abstract
Autophagy has recently been implicated in both the prevention and progression of cancer. However, the molecular basis for the relationship between autophagy induction and the initial acquisition of malignancy is currently unknown. Here, we provide the first evidence that autophagy is essential for oncogenic K-Ras (K-Ras(V12))-induced malignant cell transformation. Retroviral expression of K-Ras(V12) induced autophagic vacuole formation and malignant transformation in human breast epithelial cells. Interestingly, pharmacological inhibition of autophagy completely blocked K-Ras(V12)-induced, anchorage-independent cell growth on soft agar. Both mRNA and protein levels of ATG5 and ATG7 (autophagy-specific genes 5 and 7, respectively) were increased in cells overexpressing K-Ras(V12). Targeted suppression of ATG5 or ATG7 expression by short hairpin (sh) RNA inhibited cell growth on soft agar and tumor formation in nude mice. Moreover, inhibition of reactive oxygen species (ROS) with antioxidants clearly attenuated K-Ras(V12)-induced ATG5 and ATG7 induction, autophagy, and malignant cell transformation. MAPK pathway components were activated in cells overexpressing K-Ras(V12), and inhibition of JNK blunted induction of ATG5 and ATG7 and subsequent autophagy. In addition, pretreatment with antioxidants completely inhibited K-Ras(V12)-induced JNK activation. Our results provide novel evidence that autophagy is critically involved in malignant transformation by oncogenic K-Ras and show that reactive oxygen species-mediated JNK activation plays a causal role in autophagy induction through up-regulation of ATG5 and ATG7.
Collapse
Affiliation(s)
- Min-Jung Kim
- From the Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, 17 Haengdang-Dong, Seongdong-Ku, Seoul 133-791, Korea
| | - Soo-Jung Woo
- From the Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, 17 Haengdang-Dong, Seongdong-Ku, Seoul 133-791, Korea
| | - Chang-Hwan Yoon
- From the Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, 17 Haengdang-Dong, Seongdong-Ku, Seoul 133-791, Korea
| | - Jae-Seong Lee
- From the Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, 17 Haengdang-Dong, Seongdong-Ku, Seoul 133-791, Korea
| | - Sungkwan An
- the Department of Microbiological Engineering, Kon-Kuk University, Seoul 143-701, Korea
| | - Yung-Hyun Choi
- the Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Korea
| | - Sang-Gu Hwang
- the Division of Radiation Cancer Biology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea, and
| | - Gyesoon Yoon
- the Department of Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 443-721, Korea
| | - Su-Jae Lee
- From the Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, 17 Haengdang-Dong, Seongdong-Ku, Seoul 133-791, Korea
| |
Collapse
|
|
49
|
Horbinski C, Mojesky C, Kyprianou N. Live free or die: tales of homeless (cells) in cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 177:1044-52. [PMID: 20639456 DOI: 10.2353/ajpath.2010.091270] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Anoikis, programed cell death that occurs on cell detachment from the extracellular matrix, thus disrupting integrin-ligand interactions, is a critical mechanism in preventing ectopic cell growth or attachment to an inappropriate matrix. Anoikis prevents shed epithelial cells from colonizing elsewhere and is thus essential for maintaining tissue organization. Lack of integrin ligation leads to decreased focal adhesion kinase and integrin-linked kinase activity, which impairs downstream survival signaling. Consequently, targeting tumor cell survival by triggering anoikis provides a unique molecular basis for novel therapeutic targeting of tumors before initiation of metastasis. The two major cell death pathways involved in anoikis signaling are apoptosis and autophagy; growing evidence suggests an extensive cross-talk between the two killing modes as well as context-dependent cooperation and antagonism. This review discusses the functional integration between the two modes of cell death converging at anoikis, including key molecules of interaction such as Beclin 1, reactive oxygen species, extracellular signal-related kinase, and death-associated protein kinase. The involvement of other apoptotic effectors such as Bcl-2, p53, and FLICE inhibitory protein in cancer cell anoikis is also discussed. Dissecting the mechanistic players in the cellular response may be of high clinical significance in identifying effective approaches in reversing anoikis resistance in primary tumor cells and, consequently, impairing metastasis.
Collapse
Affiliation(s)
- Craig Horbinski
- Department of Pathology, University of Kentucky, Lexington, Kentucky, USA
| | | | | |
Collapse
|