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Yang X, Cao X, Zhu Q. p62/SQSTM1 in cancer: phenomena, mechanisms, and regulation in DNA damage repair. Cancer Metastasis Rev 2025; 44:33. [PMID: 39954143 PMCID: PMC11829845 DOI: 10.1007/s10555-025-10250-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 02/06/2025] [Indexed: 02/17/2025]
Abstract
The multidomain protein cargo adaptor p62, also known as sequestosome 1, serves as a shuttling factor and adaptor for the degradation of substrates via the proteasome and autophagy pathways. Regarding its structure, p62 is composed of several functional domains, including the N-terminal Phox1 and Bem1p domains, a ZZ-type zinc finger domain, a LIM protein-binding domain that contains the tumor necrosis factor receptor-associated factor 6 (TRAF6) binding region, two nuclear localization signals (NLS 1/2), a nuclear export signal (NES), the LC3-interacting region (LIR), a Kelch-like ECH-associated protein 1 (KEAP1)-interacting region, and a ubiquitin-associated (UBA) domain. Recent studies have highlighted the critical role of p62 in the development and progression of various malignancies. Overexpression and/or impaired degradation of p62 are linked to the initiation and progression of numerous cancers. While p62 is primarily localized in the cytosol and often considered a cytoplasmic protein, most of the existing literature focuses on its cytoplasmic functions, leaving its nuclear roles less explored. However, an increasing body of research has uncovered p62's involvement in the cellular response to DNA damage. In this review, we summarize the current understanding of p62's molecular functions in malignancies, with particular emphasis on its role in DNA damage repair, highlighting the latest advances in this field.
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Affiliation(s)
- Xiaojuan Yang
- Liver Digital Transformation Research Laboratory, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, Sichuan, 610041, People's Republic of China
| | - Xunjie Cao
- Division of Abdominal Tumor Multimodality Treatment, Department of General Surgery, West China Hospital, Sichuan University, Cancer Center, Chengdu, 610041, China
| | - Qing Zhu
- Division of Abdominal Tumor Multimodality Treatment, Department of General Surgery, West China Hospital, Sichuan University, Cancer Center, Chengdu, 610041, China.
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Taha SR, Karimi M, Mahdavi B, Yousefi Tehrani M, Bemani A, Kabirian S, Mohammadi J, Jabbari S, Hushmand M, Mokhtar A, Pourhanifeh MH. Crosstalk between non-coding RNAs and programmed cell death in colorectal cancer: implications for targeted therapy. Epigenetics Chromatin 2025; 18:3. [PMID: 39810224 PMCID: PMC11734566 DOI: 10.1186/s13072-024-00560-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 11/13/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Colorectal cancer (CRC) remains one of the most common causes of cancer-related mortality worldwide. Its progression is influenced by complex interactions involving genetic, epigenetic, and environmental factors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been identified as key regulators of gene expression, affecting diverse biological processes, notably programmed cell death (PCD). OBJECTIVE This review aims to explore the relationship between ncRNAs and PCD in CRC, focusing on how ncRNAs influence cancer cell survival, proliferation, and treatment resistance. METHODS A comprehensive literature analysis was conducted to examine recent findings on the role of ncRNAs in modulating various PCD mechanisms, including apoptosis, autophagy, necroptosis, and pyroptosis, and their impact on CRC development and therapeutic response. RESULTS ncRNAs were found to significantly regulate PCD pathways, impacting tumor growth, metastasis, and treatment sensitivity in CRC. Their influence on these pathways highlights the potential of ncRNAs as biomarkers for early CRC detection and as targets for innovative therapeutic interventions. CONCLUSION Understanding the involvement of ncRNAs in PCD regulation offers new insights into CRC biology. The targeted modulation of ncRNA-PCD interactions presents promising avenues for personalized cancer treatment, which may improve patient outcomes by enhancing therapeutic effectiveness and reducing resistance.
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Affiliation(s)
- Seyed Reza Taha
- Department of Pathology and Immunology, Washington University School of Medicine, St. LouisWashington, MO, USA
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Karimi
- Faculty of Medicine, Bogomolets National Medical University (NMU), Kiev, Ukraine.
| | - Bahar Mahdavi
- Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | | | - Ali Bemani
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Shahriar Kabirian
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Javad Mohammadi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Sina Jabbari
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Meysam Hushmand
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Alireza Mokhtar
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Hossein Pourhanifeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
- PAKAN Institute, Tehran, Iran.
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de Oliveira Silva N, de Lima LVA, de Oliveira LM, da Silva MF, de Aguiar AP, Semprebon SC, Favaron PO, Lepri SR, Felicidade I, Mantovani MS. Cellular and molecular antiproliferative effects in 2D monolayer and 3D-cultivated HT-29 cells treated with zerumbone. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:1561-1573. [PMID: 37672080 DOI: 10.1007/s00210-023-02701-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/29/2023] [Indexed: 09/07/2023]
Abstract
Zerumbone (ZER) is a phytochemical isolated from plants of the Zingiberaceae family. Numerous studies have demonstrated its diverse pharmacological properties, particularly its potent antitumorigenic activity. This study aimed to assess the antiproliferative effects of ZER on HT-29 cells cultivated in both two-dimensional (2D) monolayer and three-dimensional (3D) spheroid culture systems. The evaluation of growth (size), cell death, and cell cycle arrest in 3D spheroid HT-29 cells was correlated with mRNA expression data. Treatment of 2D cells revealed that ZER exhibited cytotoxicity at concentrations above 30 µM, and an IC50 of 83.54 µM (24-h post-ZER treatment) effectively suppressed cell migration. In the 3D model, ZER induced an increase in spheroid volume over a 72-h period attributed to disaggregation and reconfiguration of characteristic zones. Analysis of cell death demonstrated a significant rise in apoptotic cells after 24 h of ZER treatment, along with cell cycle arrest in the G1 phase. Furthermore, ZER treatment resulted in alterations in mRNA expression, affecting key signaling pathways involved in cell death (BCL2 and BBC3), endoplasmic reticulum stress (ERN1), DNA damage (GADD45A), cell cycle regulation (CDKN1A, NFKB1, MYC, and TP53), and autophagy (BECN1 and SQSTM1). These findings suggested that ZER holds promise as a potential candidate for the development of novel anticancer agents that can modulate crucial cell signaling pathways. Additionally, the use of the 3D culture system proved to be a valuable tool in our investigation.
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Affiliation(s)
- Nayane de Oliveira Silva
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Luan Vitor Alves de Lima
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Liana Martins de Oliveira
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Matheus Felipe da Silva
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Amanda Passuello de Aguiar
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Simone Cristine Semprebon
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Phelipe Oliveira Favaron
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Sandra Regina Lepri
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Ingrid Felicidade
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil
| | - Mario Sergio Mantovani
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Paraná, Brazil.
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Noh SG, Ahn A, Davi SM, Lepley LK, Kwon OS. Quadriceps muscle atrophy after non-invasive anterior cruciate ligament injury: evidence linking to autophagy and mitophagy. Front Physiol 2024; 15:1341723. [PMID: 38496299 PMCID: PMC10940348 DOI: 10.3389/fphys.2024.1341723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 02/20/2024] [Indexed: 03/19/2024] Open
Abstract
Introduction: Anterior cruciate ligament (ACL) injury is frequently accompanied by quadriceps muscle atrophy, a process closely linked to mitochondrial health and mitochondria-specific autophagy. However, the temporal progression of key quadricep atrophy-mediating events following ACL injury remains poorly understood. To advance our understanding, we conducted a longitudinal study to elucidate key parameters in quadriceps autophagy and mitophagy. Methods: Long-Evans rats were euthanized at 7, 14, 28, and 56 days after non-invasive ACL injury that was induced via tibial compression overload; controls were not injured. Vastus lateralis muscle was extracted, and subsequent immunoblotting analysis was conducted using primary antibodies targeting key proteins involved in autophagy and mitophagy cellular processes. Results: Our findings demonstrated dynamic changes in autophagy and mitophagy markers in the quadriceps muscle during the recovery period after ACL injury. The early response to the injury was characterized by the induction of autophagy at 14 days (Beclin1), indicating an initial cellular response to the injury. Subsequently, at 14 days we observed increase in the elongation of autophagosomes (Atg4B), suggesting a potential remodeling process. The autophagosome flux was also augmented between 14- and 28 days (LC3-II/LC3-I ratio and p62). Notably, at 56 days, markers associated with the elimination of damaged mitochondria were elevated (PINK1, Parkin, and VDAC1), indicating a possible ongoing cellular repair and restoration process. Conclusion: These data highlight the complexity of muscle recovery after ACL injury and underscore the overlooked but crucial role of autophagy and mitophagy in promoting the recovery process.
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Affiliation(s)
- Sung Gi Noh
- Department of Kinesiology, University of Connecticut, Storrs, CT, United States
| | - Ahram Ahn
- Department of Kinesiology, University of Connecticut, Storrs, CT, United States
| | - Steven M. Davi
- Department of Kinesiology, University of Connecticut, Storrs, CT, United States
- Cooperative Studies Program Coordinating Center (CSPCC), VA Connecticut Healthcare System, West Haven, CT, United States
| | - Lindsey K. Lepley
- School of Kinesiology, University of Michigan, Ann Arbor, MI, United States
| | - Oh Sung Kwon
- Department of Kinesiology, University of Connecticut, Storrs, CT, United States
- Department of Orthopaedic Surgery and Center on Aging, University of Connecticut School of Medicine, Farmington, CT, United States
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Xu Y, Zhu C, Zhu C, Peng L, Ji D, Wu Q, Bai P, Bai Z, Da M. SQSTM1/p62 promotes the progression of gastric cancer through epithelial-mesenchymal transition. Heliyon 2024; 10:e24409. [PMID: 38322900 PMCID: PMC10844054 DOI: 10.1016/j.heliyon.2024.e24409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 12/25/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
Background SQSTM1/p62 is an autophagy-related receptor protein that participates in regulating tumorigenesis and multiple signaling pathways. Gastric cancer (GC) is a common tumor in the digestive tract and continues to pose a significant threat to human health. Therefore, this study aims to investigate the impact of p62 on gastric cancer. Methods Immunohistochemistry and Western blotting were employed to assess the expression level of the p62 protein in gastric cancer tissues and its correlation with prognosis. Subsequently, in vitro cell experiments were conducted to determine the role of p62 in gastric cancer cell proliferation, migration, and metastasis. Result The expression of p62 in gastric cancer tissues was significantly higher than in normal tissues. The expression of p62 was positively correlated with poor prognosis in gastric cancer patients. In vitro cell experiments indicated that p62 promotes gastric cancer cell proliferation and migration. Mechanistically, elevated p62 expression induced epithelial-mesenchymal transition (EMT), leading to upregulation of E-cadherin and downregulation of N-cadherin and vimentin. Conclusion This study provides novel and robust evidence for the mechanism by which elevated p62 expression promotes the progression of gastric cancer. It offers promising therapeutic targets for anti-tumor treatment strategies in gastric cancer patients.
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Affiliation(s)
- Yan Xu
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou,730000, China
| | - Ciba Zhu
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou,730000, China
| | - Chenglou Zhu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Lingzhi Peng
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Dandan Ji
- The First School of Clinical Medicine, Gansu University of Chinese Medicine, Lanzhou,730000, China
| | - Qiong Wu
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
| | - Pengwei Bai
- Clinical Medical College of Ningxia Medical University, 750000, Yinchuan, China
| | - Zhaozhao Bai
- Clinical Medical College of Ningxia Medical University, 750000, Yinchuan, China
| | - Mingxu Da
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, China
- Department of Surgical Oncology, Gansu Provincial Hospital, Lanzhou, 730000, China
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Zitkute V, Jasinevicius A, Vaitiekaite G, Kukcinaviciute E, Aleksandraviciute B, Eidenaite E, Sudeikis L, Jonusiene V, Sasnauskiene A. The role of p62 in cell death and survival of 5-fluorouracil and oxaliplatin-resistant colorectal cancer cells. J Cell Biochem 2023; 124:1779-1791. [PMID: 37842885 DOI: 10.1002/jcb.30488] [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: 08/09/2023] [Revised: 09/19/2023] [Accepted: 09/29/2023] [Indexed: 10/17/2023]
Abstract
The protein sequestosome 1 (p62/SQSTM1) is primarily known as a selective autophagy cargo receptor, but due to its multidomain structure, it also has roles in the ubiquitin-proteasome system, metabolism, cell death and survival signalling. The increase in p62 levels is detected in some types of cancers, including colorectal cancer (CRC). Chemoresistance is the main cause of high mortality rates of CRC patients. Since p62 can regulate both cell survival and death, it is a potential modulator of chemoresistance. The impact of p62 on molecular causes of chemoresistance in CRC cells is insufficiently analysed. Therefore, we aimed to determine the impact of p62 on apoptosis, RIPK1-pRIPK3 axis, and IL-8 levels in chemoresistant CRC cells. Our data revealed that p62 levels are higher in the 5-fluorouracil (5-FU)-resistant HCT116/FU subline compared to the parental cell line. 5-FU and oxaliplatin (OxaPt) treatment decreased p62 protein levels and it correlated with chemoresistance of HCT116 and DLD1 cell lines. The silencing of p62 increased CRC cell sensitivity to 5-FU and OxaPt, hence p62 is one of the factors supporting chemoresistance. The downregulation of p62 reduced the activation of caspase-3 and the levels of RIPK1 and pRIPK3. Furthermore, p62 silencing decreased the BAX/BCL2 ratio in the HCT116/FU subline and did not change the levels of apoptosis. Instead, p62 silencing reduced the amount of IL-8 protein. Our results show that p62 impacts chemoresistance by stimulating prosurvival signalling.
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Affiliation(s)
- Vilmante Zitkute
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Andrius Jasinevicius
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Guoda Vaitiekaite
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Egle Kukcinaviciute
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Bernadeta Aleksandraviciute
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Eigile Eidenaite
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Lukas Sudeikis
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Violeta Jonusiene
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
| | - Ausra Sasnauskiene
- Department of Biochemistry and Molecular Biology, Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania
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Abdelmaksoud NM, Abulsoud AI, Abdelghany TM, Elshaer SS, Rizk SM, Senousy MA. Mitochondrial remodeling in colorectal cancer initiation, progression, metastasis, and therapy: A review. Pathol Res Pract 2023; 246:154509. [PMID: 37182313 DOI: 10.1016/j.prp.2023.154509] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 04/25/2023] [Accepted: 05/05/2023] [Indexed: 05/16/2023]
Abstract
Colorectal cancer (CRC) is a major health concern with multifactorial pathophysiology representing intense therapeutic challenges. It is well known that deregulation of spatiotemporally-controlled signaling pathways and their metabolic reprogramming effects play a pivotal role in the development and progression of CRC. As such, the mitochondrial role in CRC initiation gained a lot of attention recently, as it is considered the powerhouse that regulates the bioenergetics in CRC. In addition, the crosstalk between microRNAs (miRNAs) and mitochondrial dysfunction has become a newfangled passion for deciphering CRC molecular mechanisms. This review sheds light on the relationship between different signaling pathways involved in metabolic reprogramming and their therapeutic targets, alterations in mitochondrial DNA content, mitochondrial biogenesis, and mitophagy, and the role of polymorphisms in mitochondrial genes as well as miRNAs regulating mitochondrial proteins in CRC initiation, progression, metastasis, and resistance to various therapies.
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Affiliation(s)
- Nourhan M Abdelmaksoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Ahmed I Abulsoud
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11823, Egypt.
| | - Tamer M Abdelghany
- Department of Pharmacology and Toxicology, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Shereen Saeid Elshaer
- Department of Biochemistry, Faculty of Pharmacy, Heliopolis University, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo 11823, Egypt
| | - Sherine Maher Rizk
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt.
| | - Mahmoud A Senousy
- Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt; Department of Biochemistry, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo 11786, Egypt
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Fu AB, Xiang SF, He QJ, Ying MD. Kelch-like proteins in the gastrointestinal tumors. Acta Pharmacol Sin 2023; 44:931-939. [PMID: 36266566 PMCID: PMC10104798 DOI: 10.1038/s41401-022-01007-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 09/22/2022] [Indexed: 11/08/2022]
Abstract
Gastrointestinal tumors have become a worldwide health problem with high morbidity and poor clinical outcomes. Chemotherapy and surgery, the main treatment methods, are still far from meeting the treatment needs of patients, and targeted therapy is in urgent need of development. Recently, emerging evidence suggests that kelch-like (KLHL) proteins play essential roles in maintaining proteostasis and are involved in the progression of various cancers, functioning as adaptors in the E3 ligase complex and promoting the specific degradation of substrates. Therefore, KLHL proteins should be taken into consideration for targeted therapy strategy discovery. This review summarizes the current knowledge of KLHL proteins in gastrointestinal tumors and discusses the potential of KLHL proteins as potential drug targets and prognostic biomarkers.
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Affiliation(s)
- An-Bo Fu
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, 310002, China
- Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310002, China
| | - Sen-Feng Xiang
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
| | - Qiao-Jun He
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Cancer Center, Zhejiang University, Hangzhou, 310058, China.
| | - Mei-Dan Ying
- Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
- Cancer Center, Zhejiang University, Hangzhou, 310058, China.
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Kalid O, Gotliv I, Levy-Apter E, Beker DF, Cherniavsky-Lev M, Rotem E, Miron N. PTX80, A Novel Compound Targeting the Autophagy Receptor p62/SQSTM1 for Treatment of Cancer. Chem Biol Drug Des 2022; 100:623-638. [PMID: 35322538 DOI: 10.1111/cbdd.14046] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 02/18/2022] [Accepted: 03/13/2022] [Indexed: 11/29/2022]
Abstract
Cancer cells are dependent on protein quality-control mechanisms, including protein chaperones, the ubiquitin proteasome system (UPS), and autophagy. The p62 receptor is a classical, ubiquitously-expressed receptor, involved in many signal transduction pathways. Upregulation and/or reduced degradation of p62 have been implicated in tumor formation and resistance to therapy. PTX80 is a first-in-class novel inhibitor of protein degradation, developed by Pi Therapeutics for treatment of cancer. PTX80 binds to p62, inducing a decrease in soluble p62 and formation of insoluble p62 aggregates, as well as failure of polyubiquitinated proteins to colocalize with p62. PTX80 induces proteotoxic stress and activation of unfolded protein response (UPR), which, in turn, leads to apoptosis. Targeting p62, which is a major protein degradation hub, may serve as a novel and beneficial strategy for treatment of cancer.
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Affiliation(s)
- Ori Kalid
- Pi Therapeutics, 45 HaMelacha St., 2nd Floor, Netanya, Israel, 4250574
| | - Irina Gotliv
- Pi Therapeutics, 45 HaMelacha St., 2nd Floor, Netanya, Israel, 4250574
| | - Einat Levy-Apter
- Pi Therapeutics, 45 HaMelacha St., 2nd Floor, Netanya, Israel, 4250574
| | | | | | - Etai Rotem
- Pi Therapeutics, 45 HaMelacha St., 2nd Floor, Netanya, Israel, 4250574
| | - Naama Miron
- Pi Therapeutics, 45 HaMelacha St., 2nd Floor, Netanya, Israel, 4250574
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Tang J, Li Y, Xia S, Li J, Yang Q, Ding K, Zhang H. Sequestosome 1/p62: A multitasker in the regulation of malignant tumor aggression (Review). Int J Oncol 2021; 59:77. [PMID: 34414460 PMCID: PMC8425587 DOI: 10.3892/ijo.2021.5257] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
Sequestosome 1 (SQSTM1)/p62 is an adapter protein mainly involved in the transportation, degradation and destruction of various proteins that cooperates with components of autophagy and the ubiquitin‑proteasome degradation pathway. Numerous studies have shown that SQSTM1/p62 functions at multiple levels, including involvement in genetic stability or modification, post‑transcriptional regulation and protein function. As a result, SQSTM1/p62 is a versatile protein that is a critical core regulator of tumor cell genetic stability, autophagy, apoptosis and other forms of cell death, malignant growth, proliferation, migration, invasion, metastasis and chemoradiotherapeutic response, and an indicator of patient prognosis. SQSTM1/p62 regulates these processes via its distinct molecular structure, through which it participates in a variety of activating or inactivating tumor‑related and tumor microenvironment‑related signaling pathways, particularly positive feedback loops and epithelial‑mesenchymal transition‑related pathways. Therefore, functioning as a proto‑oncogene or tumor suppressor gene in various types of cancer and tumor‑associated microenvironments, SQSTM1/p62 is capable of promoting or retarding malignant tumor aggression, giving rise to immeasurable effects on tumor occurrence and development, and on patient treatment and prognosis.
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Affiliation(s)
- Jinlong Tang
- Department of Pathology and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Yuan Li
- Department of Pediatrics, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310000, P.R. China
| | - Shuli Xia
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang 310058, P.R. China
- Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang 310058, P.R. China
| | - Jinfan Li
- Department of Pathology and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Qi Yang
- Department of Pathology and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Kefeng Ding
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Honghe Zhang
- Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang 310058, P.R. China
- Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, Zhejiang 310058, P.R. China
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11
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Wu Q, Xiang M, Wang K, Chen Z, Long L, Tao Y, Liang Y, Yan Y, Xiao Z, Qiu S, Yi B. Overexpression of p62 Induces Autophagy and Promotes Proliferation, Migration and Invasion of Nasopharyngeal Carcinoma Cells through Promoting ERK Signaling Pathway. Curr Cancer Drug Targets 2021; 20:624-637. [PMID: 32329689 DOI: 10.2174/1568009620666200424145122] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 02/02/2020] [Accepted: 03/03/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Increasing evidence has shown that p62 plays an important role in tumorigenesis. However, relatively little is known about the association between p62 and tumor invasion and metastasis; in addition, its role in NPC (nasopharyngeal carcinoma, NPC) has been rarely investigated. OBJECTIVE To investigate the effect of p62 on tumorigenesis and metastasis in nasopharyngeal carcinoma. METHODS Western blotting, immunofluorescent staining and immunohistochemistry were used to evaluate p62 protein expression. Subsequently, cell viability, colony formation, migration, invasion and autophagy assays were performed. anti-p62 autoantibodies in sera were detected by ELISA. These data were correlated with clinicopathological parameters. RESULTS We confirmed that p62 was significantly up-regulated in NPC tissues. Furthermore, high expression of p62 was observed in NPC cell lines, and especially in the highly metastatic 5-8F cells. In vitro, down-regulation of p62 inhibited proliferation, clone forming ability, autophagy, migration, and invasion in 5-8F cells, whereas p62 overexpression resulted in the opposite effects in 6-10B cells. Moreover, we confirmed that p62 promotes NPC cell proliferation, migration, and invasion by activating ERK (extracellular signal-regulated kinase, ERK). Clinical analysis indicated that high p62 expression correlates with lymph node and distant metastasis (P<0.05). Serum anti-p62 autoantibodies were increased in NPC patients and levels were associated with metastasis. CONCLUSION Our data establish p62 targeting ERK as potential determinant in the NPC, which supplies a new pathway to treat NPC. Furthermore, p62 is a potential biomarker which might be closely related to the tumorigenesis and metastasis in NPC.
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Affiliation(s)
- Qiong Wu
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Manlin Xiang
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Kun Wang
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Zhen Chen
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Lu Long
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Ya Tao
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Yunlai Liang
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Yahui Yan
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Zhiqiang Xiao
- Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shiyang Qiu
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
| | - Bin Yi
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
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12
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Gong L, Wang K, Wang M, Hu R, Li H, Gao D, Lin M. CUL5-ASB6 Complex Promotes p62/SQSTM1 Ubiquitination and Degradation to Regulate Cell Proliferation and Autophagy. Front Cell Dev Biol 2021; 9:684885. [PMID: 34164402 PMCID: PMC8215545 DOI: 10.3389/fcell.2021.684885] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/06/2021] [Indexed: 12/30/2022] Open
Abstract
p62/SQSTM1 (sequestosome-1) is a key protein involved in multiple cellular bioprocesses including autophagy, nutrient sensing, cell growth, cell death, and survival. Therefore, it is implicated in human diseases such as obesity and cancer. Here, we show that the CUL5–ASB6 complex is a ubiquitin E3 ligase complex mediating p62 ubiquitination and degradation. Depletion of CUL5 or ASB6 induced p62 accumulation, and overexpression of ASB6 promoted ubiquitination and degradation of p62. Functionally, ASB6 overexpression can inhibit the proliferation of MEF and hepatocellular carcinoma cells by reducing p62 protein level, and impair the occurrence of autophagy. Overall, our study identified a new molecular mechanism regulating p62 stability, which may provide additional insights for understanding the delicate control of p62 and cell proliferation–autophagy control in physiological and pathological settings.
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Affiliation(s)
- Liyan Gong
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kaihua Wang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Mengcheng Wang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Ronggui Hu
- University of Chinese Academy of Sciences, Beijing, China.,State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Huaguang Li
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
| | - Daming Gao
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Moubin Lin
- Center for Clinical Research and Translational Medicine, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China.,Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China
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13
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Luo J, Xu T, Sun K. N6-Methyladenosine RNA Modification in Inflammation: Roles, Mechanisms, and Applications. Front Cell Dev Biol 2021; 9:670711. [PMID: 34150765 PMCID: PMC8213350 DOI: 10.3389/fcell.2021.670711] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 05/10/2021] [Indexed: 12/21/2022] Open
Abstract
N6-methyladenosine (m6A) is the most prevalent internal mRNA modification. m6A can be installed by the methyltransferase complex and removed by demethylases, which are involved in regulating post-transcriptional expression of target genes. RNA methylation is linked to various inflammatory states, including autoimmunity, infection, metabolic disease, cancer, neurodegenerative diseases, heart diseases, and bone diseases. However, systematic knowledge of the relationship between m6A modification and inflammation in human diseases remains unclear. In this review, we will discuss the association between m6A modification and inflammatory response in diseases, especially the role, mechanisms, and potential clinical application of m6A as a biomarker and therapeutic target for inflammatory diseases.
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Affiliation(s)
- Jiahui Luo
- The Center for Biomedical Research, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Xu
- Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Sun
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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14
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Bian S, Zhao Y, Li F, Lu S, Yang S, Liu M, Wang S, Zhao D, Zhang W, Wang J. Knockdown of p62/sequestosome enhances ginsenoside Rh2-induced apoptosis in cervical cancer HeLa cells with no effect on autophagy. Biosci Biotechnol Biochem 2021; 85:1097-1103. [PMID: 33784737 DOI: 10.1093/bbb/zbab019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 01/22/2021] [Indexed: 12/30/2022]
Abstract
p62/sequestosome is a multifunctional adaptor protein that participates in a wide variety of cellular processes. 20(S)-Ginsenoside Rh2 (G-Rh2) has various biological effects, including anticancer activity. We found that G-Rh2 can induce apoptosis and autophagy in HeLa cells. G-Rh2 significantly enhanced the transcriptional level of p62. A siRNA was constructed to knock down p62 and assess its effect on apoptosis induced by G-Rh2. p62 protein levels were successfully downregulated in cells transfected with the p62-specific siRNA. Silencing of p62 further decreased cell viability while also enhancing cell apoptosis, reactive oxygen species generation, the ratio of Bax to Bcl-2, and the cleavage of PARP. p62 knockdown decreased expression levels of Nrf2. Moreover, silencing of p62 had no significant effect on autophagy induced by G-Rh2. These results suggest that combining G-Rh2 treatment with inhibition of p62 may be a potential treatment strategy for cervical cancer.
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Affiliation(s)
- Shuai Bian
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Yue Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Fangyu Li
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Shuyan Lu
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Song Yang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Meichen Liu
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Siming Wang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Daqing Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Wei Zhang
- Office of Academic Research, Changchun University of Chinese Medicine, Changchun, Jilin, China
| | - Jiawen Wang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, Jilin, China
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15
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Chen L, He M, Zhang M, Sun Q, Zeng S, Zhao H, Yang H, Liu M, Ren S, Meng X, Xu H. The Role of non-coding RNAs in colorectal cancer, with a focus on its autophagy. Pharmacol Ther 2021; 226:107868. [PMID: 33901505 DOI: 10.1016/j.pharmthera.2021.107868] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 04/16/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is one of malignant afflictions burdening people worldwide, mainly caused by shortages of effective medical intervention and poorly mechanistic understanding of the pathogenesis of CRC. Non-coding RNAs (ncRNAs) are a type of heterogeneous transcripts without the capability of coding protein, but have the potency of regulating protein-coding gene expression. Autophagy is an evolutionarily conserved catabolic process in which cytoplasmic contents are delivered to cellular lysosomes for degradation, resulting in the turnover of cellular components and producing energy for cell functions. A growing body of evidence reveals that ncRNAs, autophagy, and the crosstalks of ncRNAs and autophagy play intricate roles in the initiation, progression, metastasis, recurrence and therapeutic resistance of CRC, which confer ncRNAs and autophagy to serve as clinical biomarkers and therapeutic targets for CRC. In this review, we sought to delineate the complicated roles of ncRNAs, mainly including miRNAs, lncRNAs and circRNAs, in the pathogenesis of CRC, particularly focus on the regulatory role of ncRNAs in CRC-related autophagy, attempting to shed light on the complex pathological mechanisms, involving ncRNAs and autophagy, responsible for CRC tumorigenesis and development, so as to underpin the ncRNAs- and autophagy-based therapeutic strategies for CRC in clinical setting.
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Affiliation(s)
- Li Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Man He
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Meng Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qiang Sun
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Sha Zeng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Hui Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Han Yang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Maolun Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shan Ren
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Xianli Meng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Innovative Institute of Chinese Medicine and Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Haibo Xu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; Department of Pharmacology, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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16
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Zhang B, Liu L. Autophagy is a double-edged sword in the therapy of colorectal cancer. Oncol Lett 2021; 21:378. [PMID: 33777202 PMCID: PMC7988732 DOI: 10.3892/ol.2021.12639] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 01/14/2021] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer is one of the leading causes of cancer-associated mortality worldwide. The limitations of colorectal cancer treatment include various types of multidrug resistance and the contingent damage to neighboring normal cells caused by chemotherapy. Macroautophagy/autophagy and apoptosis are essential mechanisms involved in cancer cell regulation of chemotherapy. Autophagy can either cause cancer cell death or promote tumor survival during colorectal cancer. Given that autophagy is involved in chemotherapy of colorectal cancer, an improved insight into the potential interactions between apoptosis and autophagy is crucial. The present review aimed to summarize the involvement of autophagy in the regulation of colorectal cancer and its association with chemotherapy. Furthermore, the role of natural product extraction, novel chemicals and small molecules, as well as radiation, which induce autophagy in colorectal cancer cells, were reviewed. Finally, the present review aimed to provide an outlook for the regulation of autophagy as a novel approach to the treatment of cancer, particularly chemotherapy-resistant colorectal cancer.
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Affiliation(s)
- Bo Zhang
- Medical Laboratory for Radiation Research, Beijing Institute for Occupational Disease Prevention and Treatment, Beijing 100093, P.R. China.,College of Food Science and Engineering, Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Lantao Liu
- Medical Laboratory for Radiation Research, Beijing Institute for Occupational Disease Prevention and Treatment, Beijing 100093, P.R. China
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17
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Suares A, Medina MV, Coso O. Autophagy in Viral Development and Progression of Cancer. Front Oncol 2021; 11:603224. [PMID: 33763351 PMCID: PMC7982729 DOI: 10.3389/fonc.2021.603224] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.
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Affiliation(s)
- Alejandra Suares
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María Victoria Medina
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Omar Coso
- Departamento de Fisiología y Biología Molecular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET—Universidad de Buenos Aires, Buenos Aires, Argentina
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18
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Suares A, Medina MV, Coso O. Autophagy in Viral Development and Progression of Cancer. Front Oncol 2021. [DOI: 10.3389/fonc.2021.603224
expr 816899697 + 824303767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Autophagy is a complex degradative process by which eukaryotic cells capture cytoplasmic components for subsequent degradation through lysosomal hydrolases. Although this catabolic process can be triggered by a great variety of stimuli, action in cells varies according to cellular context. Autophagy has been previously linked to disease development modulation, including cancer. Autophagy helps suppress cancer cell advancement in tumor transformation early stages, while promoting proliferation and metastasis in advanced settings. Oncoviruses are a particular type of virus that directly contribute to cell transformation and tumor development. Extensive molecular studies have revealed complex ways in which autophagy can suppress or improve oncovirus fitness while still regulating viral replication and determining host cell fate. This review includes recent advances in autophagic cellular function and emphasizes its antagonistic role in cancer cells.
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19
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Tamura K, Watanabe K, Matsushita Y, Watanabe H, Motoyama D, Ito T, Sugiyama T, Otsuka A, Miyake H. Enhanced Sensitivity to NVP-BEZ235 by Inhibition of p62/SQSTM1 in Human Bladder Cancer KoTCC-1 Cells Both In Vitro and In Vivo. In Vivo 2021; 34:1001-1008. [PMID: 32354885 DOI: 10.21873/invivo.11868] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/20/2020] [Accepted: 01/24/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIM The prognosis of patients with invasive bladder cancer remains poor. The objective of this study was to evaluate the efficacy of NVP-BEZ235 (NVP), a dual PI3K/mTOR inhibitor, combined with the inactivation of p62/SQSTM1 (p62) in a human bladder cancer KoTCC-1 model. MATERIALS AND METHODS An expression plasmid with short hairpin RNA targeted against p62 was transfected into KoTCC-1 cells (KoTCC-1/sh-p62). The antitumor effects of NVP on KoTCC-1/sh-p62 were investigated in comparison with those on KoTCC-1 transfected with a control plasmid alone (KoTCC-1/C). RESULTS KoTCC-1/sh-p62 showed significantly higher sensitivity to NVP than KoTCC-1/C. Treatment of both cell lines with NVP markedly inactivated the PI3K/Akt/mTOR signaling pathway. However, NVP treatment stimulated the autophagic pathway in KoTCC-1/C, but not in KoTCC-1/sh-p62. Furthermore, compared with KoTCC-1/C, NVP treatment induced apoptosis of KoTCC-1/sh-p62 cells, which was accompanied by significant downregulation of c-IAP-1 and XIAP as well as upregulation of Bax. Moreover, the in vivo growth of KoTCC-1/sh-p62 tumors was significantly suppressed by treatment with NVP compared to KoTCC-1/C tumors. CONCLUSION Inhibition of p62 expression combined with NVP may represent an effective therapeutic approach for patients with invasive bladder cancer.
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Affiliation(s)
- Keita Tamura
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Kyohei Watanabe
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yuto Matsushita
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiromitsu Watanabe
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Daisuke Motoyama
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Toshiki Ito
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takayuki Sugiyama
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Atsushi Otsuka
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hideaki Miyake
- Department of Urology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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20
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Life, death, and autophagy in cancer: NF-κB turns up everywhere. Cell Death Dis 2020; 11:210. [PMID: 32231206 PMCID: PMC7105474 DOI: 10.1038/s41419-020-2399-y] [Citation(s) in RCA: 226] [Impact Index Per Article: 45.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 02/27/2020] [Accepted: 03/03/2020] [Indexed: 12/15/2022]
Abstract
Escaping programmed cell death is a hallmark of cancer. NF-κB transcription factors are key regulator of cell survival and aberrant NF-κB signaling has been involved in the pathogenesis of most human malignancies. Although NF-κB is best known for its antiapoptotic role, other processes regulating the life/death balance, such as autophagy and necroptosis, seem to network with NF-κB. This review discusses how the reciprocal regulation of NF-κB, autophagy and programmed cell death affect cancer development and progression.
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21
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Tao M, Liu T, You Q, Jiang Z. p62 as a therapeutic target for tumor. Eur J Med Chem 2020; 193:112231. [PMID: 32193054 DOI: 10.1016/j.ejmech.2020.112231] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 03/10/2020] [Accepted: 03/10/2020] [Indexed: 12/21/2022]
Abstract
p62/SQSTM1 (hereafter as p62) is a stress-inducible cellular protein, which interacts with various signaling proteins to regulate a variety of cellular functions. Growing lines of evidence supported a critical role of p62 in tumorigenesis, and p62 may become a therapeutic target for tumor. In this review, we summarize biological functions of structural domains of p62, reported bioactive molecules targeting p62, and the relationship between p62 and tumorigenesis.
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Affiliation(s)
- Mengmin Tao
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Tian Liu
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Qidong You
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Zhengyu Jiang
- State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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22
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Hou B, Wang G, Gao Q, Wei Y, Zhang C, Wang Y, Huo Y, Yang H, Jiang X, Xi Z. SQSTM1/p62 loss reverses the inhibitory effect of sunitinib on autophagy independent of AMPK signaling. Sci Rep 2019; 9:11087. [PMID: 31366950 PMCID: PMC6668422 DOI: 10.1038/s41598-019-47597-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 07/19/2019] [Indexed: 02/03/2023] Open
Abstract
Sunitinib (ST), a multitargeted receptor tyrosine kinase inhibitor, has been demonstrated to be effective for the treatment of renal carcinoma. It has been reported that ST is involved in the mediation of autophagy; however, its regulatory role in the autophagic process remains controversial. Furthermore, the mechanism by which activated AMP-activated protein kinase (AMPK) negatively regulates autophagy remains nearly unexplored. In the present study, we revealed that ST inhibited AMPK activity and regulated autophagy in a cell type- and dose-dependent manner. In a number of cell lines, ST was demonstrated to inhibit H2O2-induced autophagy and the phosphorylation of acetyl-CoA carboxylase (ACC), whereas alone it could block the autophagic flux concurrent with increased expression of p62. An immunoprecipitation assay revealed that LC3 directly interacted with p62, whereas ST increased punctate LC3 staining, which was well colocalized with p62. Taken together, we reveal a previously unnoticed pathway for ST to regulate the autophagic process, and p62, although often utilized as a substrate in autophagy, plays a critical role in regulating the inhibition of ST in both basal and induced autophagy.
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Affiliation(s)
- Bolin Hou
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100039, China
| | - Gang Wang
- Department of Urology, Peking University First Hospital, Beijing, 100034, China
| | - Quan Gao
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100039, China
| | - Yanjie Wei
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100039, China
| | - Caining Zhang
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100039, China
| | - Yange Wang
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.,University of Chinese Academy of Sciences, Beijing, 100039, China
| | - Yuqing Huo
- Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, 30912, Georgia, USA
| | - Huaiyi Yang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Xuejun Jiang
- State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Zhijun Xi
- Department of Urology, Peking University First Hospital, Beijing, 100034, China.
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23
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Zhang S, Yang Z, Bao W, Liu L, You Y, Wang X, Shao L, Fu W, Kou X, Shen W, Yuan C, Hu B, Dang W, Nandakumar KS, Jiang H, Zheng M, Shen X. SNX10 (sorting nexin 10) inhibits colorectal cancer initiation and progression by controlling autophagic degradation of SRC. Autophagy 2019; 16:735-749. [PMID: 31208298 DOI: 10.1080/15548627.2019.1632122] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
The non-receptor tyrosine kinase SRC is a key mediator of cellular protumorigenic signals. SRC is aberrantly over-expressed and activated in more than 80% of colorectal cancer (CRC) patients, therefore regulation of its stability and activity is essential. Here, we report a significant down regulation of SNX10 (sorting nexin 10) in human CRC tissues, which is closely related to tumor differentiation, TNM stage, lymph node metastasis and survival period. SNX10 deficiency in normal and neoplastic colorectal epithelial cells promotes initiation and progression of CRC in mice. SNX10 controls SRC levels by mediating autophagosome-lysosome fusion and SRC recruitment for autophagic degradation. These mechanisms ensure proper controlling of the activities of SRC-STAT3 and SRC-CTNNB1 signaling pathways by up-regulating SNX10 expression under stress conditions. These findings suggest that SNX10 acts as a tumor suppressor in CRC and it could be a potential therapeutic target for future development.Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; ATG12: autophagy related 12; CQ: chloroquine; CRC: colorectal cancer; CTNNB1: catenin beta 1; EBSS: Earle's balanced salt solution; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; MAP1LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; mRNA: messenger RNA; PX: phox homology; RT-qPCR: real time quantitative polymerase chain reaction; siRNA: small interfering RNA; SNX10: sorting nexin 10; SQSTM1: sequestosome 1; SRC: SRC proto-oncogene, non-receptor tyrosine kinase; STAT3: signal transducer and activator of transcription 3; WT: wild type.
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Affiliation(s)
- Sulin Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.,Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Zhiwen Yang
- Department of Pharmacy, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Weilian Bao
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Lixin Liu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Yan You
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Xu Wang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Liming Shao
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Wei Fu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Xinhui Kou
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Weixing Shen
- The Translational Medicine Research Center, Nanjing University of Traditional Chinese Medicine, Nanjing, China
| | - Congmin Yuan
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Bin Hu
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Wenzhen Dang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | | | - Hualiang Jiang
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Mingyue Zheng
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Xiaoyan Shen
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
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24
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Nawas A, Narayanan S, Mistry R, Thomas-Jardin S, Ramachandran J, Ravichandran J, Neduvelil E, Luangpanh K, Delk NA. IL-1 induces p62/SQSTM1 and autophagy in ERα + /PR + BCa cell lines concomitant with ERα and PR repression, conferring an ERα - /PR - BCa-like phenotype. J Cell Biochem 2019; 120:1477-1491. [PMID: 30324661 PMCID: PMC6465183 DOI: 10.1002/jcb.27340] [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] [Received: 03/01/2018] [Accepted: 06/26/2018] [Indexed: 02/06/2023]
Abstract
Estrogen receptor α (ERα)low/- tumors are associated with breast cancer (BCa) endocrine resistance, where ERα low tumors show a poor prognosis and a molecular profile similar to triple negative BCa tumors. Interleukin-1 (IL-1) downregulates ERα accumulation in BCa cell lines, yet the cells can remain viable. In kind, IL-1 and ERα show inverse accumulation in BCa patient tumors and IL-1 is implicated in BCa progression. IL-1 represses the androgen receptor hormone receptor in prostate cancer cells concomitant with the upregulation of the prosurvival, autophagy-related protein, Sequestome-1 (p62/SQSTM1; hereinafter, p62); and given their similar etiology, we hypothesized that IL-1 also upregulates p62 in BCa cells concomitant with hormone receptor repression. To test our hypothesis, BCa cell lines were exposed to conditioned medium from IL-1-secreting bone marrow stromal cells (BMSCs), IL-1, or IL-1 receptor antagonist. Cells were analyzed for the accumulation of ERα, progesterone receptor (PR), p62, or the autophagosome membrane protein, microtubule-associated protein 1 light chain 3 (LC3), and for p62-LC3 interaction. We found that IL-1 is sufficient to mediate BMSC-induced ERα and PR repression, p62 and autophagy upregulation, and p62-LC3 interaction in ERα+ /PR+ BCa cell lines. However, IL-1 does not significantly elevate the high basal p62 accumulation or high basal autophagy in the ERα- /PR- BCa cell lines. Thus, our observations imply that IL-1 confers a prosurvival ERα- /PR- molecular phenotype in ERα+ /PR+ BCa cells that may be dependent on p62 function and autophagy and may underlie endocrine resistance.
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Affiliation(s)
- A.F. Nawas
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
| | - S. Narayanan
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
| | - R. Mistry
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
| | - S.E. Thomas-Jardin
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
| | - J. Ramachandran
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
| | - J. Ravichandran
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
| | - E. Neduvelil
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
| | - K. Luangpanh
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
| | - N. A. Delk
- Biological Sciences Department, University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080
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25
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Loss of the selective autophagy receptor p62 impairs murine myeloid leukemia progression and mitophagy. Blood 2018; 133:168-179. [PMID: 30498063 DOI: 10.1182/blood-2018-02-833475] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 11/26/2018] [Indexed: 12/29/2022] Open
Abstract
Autophagy maintains hematopoietic stem cell integrity and prevents malignant transformation. In addition to bulk degradation, selective autophagy serves as an intracellular quality control mechanism and requires autophagy receptors, such as p62 (SQSTM1), to specifically bridge the ubiquitinated cargos into autophagosomes. Here, we investigated the function of p62 in acute myeloid leukemia (AML) in vitro and in murine in vivo models of AML. Loss of p62 impaired expansion and colony-forming ability of leukemia cells and prolonged latency of leukemia development in mice. High p62 expression was associated with poor prognosis in human AML. Using quantitative mass spectrometry, we identified enrichment of mitochondrial proteins upon immunoprecipitation of p62. Loss of p62 significantly delayed removal of dysfunctional mitochondria, increased mitochondrial superoxide levels, and impaired mitochondrial respiration. Moreover, we demonstrated that the autophagy-dependent function of p62 is essential for cell growth and effective mitochondrial degradation by mitophagy. Our results highlight the prominent role of selective autophagy in leukemia progression, and specifically, the importance of mitophagy to maintain mitochondrial integrity.
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26
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miR675 Accelerates Malignant Transformation of Mesenchymal Stem Cells by Blocking DNA Mismatch Repair. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 14:171-183. [PMID: 30594073 PMCID: PMC6307386 DOI: 10.1016/j.omtn.2018.11.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 11/20/2018] [Accepted: 11/20/2018] [Indexed: 12/18/2022]
Abstract
miR675 is highly expressed in several human tumor tissues and positively regulates cell progression. Herein, we demonstrate that miR675 promotes malignant transformation of human mesenchymal stem cells. Mechanistically, we reveal that miR675 enhances the expression of the polyubiquitin-binding protein p62. Intriguingly, P62 competes with SETD2 to bind histone H3 and then significantly reduces SETD2-binding capacity to substrate histone H3, triggering drastically the reduction of three methylation on histone H3 36th lysine (H3K36me3). Thereby, the H3K36me3-hMSH6-SKP2 triplex complex is significantly decreased. Notably, the ternary complex’s occupancy capacity on chromosome is absolutely reduced, preventing it from DNA damage repair. By virtue of the reductive degradation ability of SKP2 for aging histone H3.3 bound to mismatch DNA, the aging histone H3.3 repair is delayed. Therefore, the mismatch DNA escapes from repair, triggering the abnormal expression of several cell cycle-related genes and causing the malignant transformation of mesenchymal stem cells. These observations strongly suggest understanding the novel functions of miR675 will help in the development of novel therapeutic approaches in a broad range of cancer types.
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27
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Peng M, Wang J, Zhang D, Jin H, Li J, Wu XR, Huang C. PHLPP2 stabilization by p27 mediates its inhibition of bladder cancer invasion by promoting autophagic degradation of MMP2 protein. Oncogene 2018; 37:5735-5748. [PMID: 29930380 PMCID: PMC6202328 DOI: 10.1038/s41388-018-0374-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/25/2018] [Accepted: 05/26/2018] [Indexed: 01/24/2023]
Abstract
Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) is a tumor suppressor that catalyzes the de-phosphorylation of the AGC kinases, while p27 acts as a tumor suppressor that regulates cell cycle, apoptosis, and cell motility. Our previous studies have identified that PHLPP2 participates in inhibition of transformation of human bronchial epithelial cells following lung carcinogen B[a]P/B[a]PDE exposure. However, nothing was known about the association of p27 with regulation of PHLPP2 expression and the role of PHLPP2 in bladder cancer (BC) invasion. In our current studies, we demonstrated that PHLPP2 inhibited BC invasion through promoting MMP2 degradation via p62-mediated autophagy; and p27 expression was able to stabilize PHLPP2 protein by inhibiting protein degradation of Hsp90, which could directly bind to PHLPP2 and protect it from degradation. More in-depth studies discovered that stabilization of Hsp90 by p27 was mediated by calpain1 proteolysis system, whereas p27 inhibited calpain1 gene transcription by attenuating Jak1/Stat1 cascade in human invasive BC cells. Collectively, we for the first time revealed PHLPP2 downregulation in BCs and its participating in promotion of BC invasion, as well as novel role of p27 and mechanisms underlying its regulation of PHLPP2 protein degradation through Hsp90-dependent manner. Our findings improve our understanding of p27 and PHLPP2 roles and their crosstalk in regulation of BC invasion, which further contributes to improve the current strategy for invasive bladder cancer therapy.
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Affiliation(s)
- Minggang Peng
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, 10987, USA
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, China
| | - Jingjing Wang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, 10987, USA
| | - Dongyun Zhang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, 10987, USA
| | - Honglei Jin
- School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Jingxia Li
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, 10987, USA
| | - Xue-Ru Wu
- Departments of Urology and Pathology, New York University School of Medicine, New York, NY, 10016, USA
| | - Chuanshu Huang
- Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY, 10987, USA.
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28
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Wang Z, Chen Q, Li B, Xie JM, Yang XD, Zhao K, Wu Y, Ye ZY, Chen ZR, Qin ZH, Xing CG. Escin-induced DNA damage promotes escin-induced apoptosis in human colorectal cancer cells via p62 regulation of the ATM/γH2AX pathway. Acta Pharmacol Sin 2018; 39:1645-1660. [PMID: 29849127 PMCID: PMC6289333 DOI: 10.1038/aps.2017.192] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Accepted: 12/29/2017] [Indexed: 12/18/2022]
Abstract
Escin, a triterpene saponin isolated from horse chestnut seed, has been used to treat encephaledema, tissue swelling and chronic venous insufficiency. Recent studies show that escin induces cell cycle arrest, tumor proliferation inhibition and tumor cell apoptosis. But the relationship between escin-induced DNA damage and cell apoptosis in tumor cells remains unclear. In this study, we investigated whether and how escin-induced DNA damage contributed to escin-induced apoptosis in human colorectal cancer cells. Escin (5-80 μg/mL) dose-dependently inhibited the cell viability and colony formation in HCT116 and HCT8 cells. Escin treatment induced DNA damage, leading to p-ATM and γH2AX upregulation. Meanwhile, escin treatment increased the expression of p62, an adaptor protein, which played a crucial role in controlling cell survival and tumorigenesis, and had a protective effect against escin-induced DNA damage: knockdown of p62 apparently enhanced escin-induced DNA damage, whereas overexpression of p62 reduced escin-induced DNA damage. In addition, escin treatment induced concentration- and time-dependent apoptosis. Similarly, knockdown of p62 significantly increased escin-induced apoptosis in vitro and produced en escin-like antitumor effect in vivo. Overexpression of p62 decreased the rate of apoptosis. Further studies revealed that the functions of p62 in escin-induced DNA damage were associated with escin-induced apoptosis, and p62 knockdown combined with the ATM inhibitor KU55933 augmented escin-induced DNA damage and further increased escin-induced apoptosis. In conclusion, our results demonstrate that p62 regulates ATM/γH2AX pathway-mediated escin-induced DNA damage and apoptosis.
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Affiliation(s)
- Zhong Wang
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China
| | - Qiang Chen
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China
| | - Bin Li
- Department of General Surgery, the First People's Hospital of Wu Jiang, Suzhou, 215200, China
| | - Jia-Ming Xie
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China
| | - Xiao-Dong Yang
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China
| | - Kui Zhao
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China
| | - Yong Wu
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China
| | - Zhen-Yu Ye
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China
| | - Zheng-Rong Chen
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China
| | - Zheng-Hong Qin
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, College of Pharmaceutical Science, Soochow University, Suzhou, 215123, China.
| | - Chun-Gen Xing
- Department of General Surgery, Second Affiliated Hospital of Soochow University, Suzhou, 215007, China.
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29
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Inflammatory-Related P62 Triggers Malignant Transformation of Mesenchymal Stem Cells through the Cascade of CUDR-CTCF-IGFII-RAS Signaling. MOLECULAR THERAPY. NUCLEIC ACIDS 2018; 11:367-381. [PMID: 29858072 PMCID: PMC5992448 DOI: 10.1016/j.omtn.2018.03.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 02/24/2018] [Accepted: 03/04/2018] [Indexed: 12/27/2022]
Abstract
Inflammatory and autophagy-related gene P62 is highly expressed in most human tumor tissues. Herein, we demonstrate that P62 promotes human mesenchymal stem cells' malignant transformation via the cascade of P62-tumor necrosis factor alpha (TNF-α)-CUDR-CTCF-insulin growth factor II (IGFII)-H-Ras signaling. Mechanistically, we reveal P62 enhances IGFII transcriptional activity through forming IGFII promoter-enhancer chromatin loop and increasing METTL3 occupancy on IGFII 3' UTR and enhances H-Ras overexpression by harboring inflammation-related factors, e.g., TNFR1, CLYD, EGR1, NFκB, TLR4, and PPARγ. Furthermore, the P62 cooperates with TNF-α to promote malignant transformation of mesenchymal stem cells. These findings, for the first time, provide insight into the positive role that P62 plays in malignant transformation of mesenchymal stem cells and reveal a novel link between P62 and the inflammation factors in mesenchymal stem cells.
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30
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Adams O, Dislich B, Berezowska S, Schläfli AM, Seiler CA, Kröll D, Tschan MP, Langer R. Prognostic relevance of autophagy markers LC3B and p62 in esophageal adenocarcinomas. Oncotarget 2018; 7:39241-39255. [PMID: 27250034 PMCID: PMC5129929 DOI: 10.18632/oncotarget.9649] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/13/2016] [Indexed: 12/12/2022] Open
Abstract
Esophageal adenocarcinomas (EAC) are aggressive tumors with considerable rates of chemoresistance. Autophagy is a lysosome-dependent degradation process, characterized by the formation of vesicles called autophagosomes, and has been implicated in cancer. Protein light chain 3 B (LC3B) and p62 are associated with autophagosomal membranes and degraded. We aimed to assess the impact of basal autophagy on EAC. In EAC cell lines, an increase in LC3B and p62 was observed with increasing concentrations of the autophagy inhibitor chloroquine, which indicates functional basal autophagy. LC3B and p62 immunohistochemistry was performed on primary resected EAC. High LC3B and p62 expression was associated with earlier tumor stages (p < 0.05). High nuclear and cytoplasmic p62 staining were associated with a better prognosis (p = 0.006; p = 0.028). Various combinations of p62 expression with or without LC3B expression identified different prognostic groups. Tumors with low total p62 (p = 0.007) or low LC3B/low p62 expression had the worst outcome (p = 0.007; p = 0.005). A combination score of dot-like/cytoplasmic p62 and nuclear p62 staining was an independent prognostic parameter (p = 0.033; HR = 0.6). This study highlights the potential significance of basal autophagy in EAC biology. Tumors with low LC3B and p62 expression show the most aggressive behavior and may be candidates for autophagy regulating therapeutics.
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Affiliation(s)
- Olivia Adams
- Institute of Pathology, University of Bern, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Bastian Dislich
- Institute of Pathology, University of Bern, Bern, Switzerland
| | | | - Anna M Schläfli
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Christian A Seiler
- Department of Visceral Surgery and Medicine, Inselspital University Hospital Bern and University of Bern, Bern, Switzerland
| | - Dino Kröll
- Department of Visceral Surgery and Medicine, Inselspital University Hospital Bern and University of Bern, Bern, Switzerland
| | - Mario P Tschan
- Institute of Pathology, University of Bern, Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Rupert Langer
- Institute of Pathology, University of Bern, Bern, Switzerland
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31
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Ramírez-Peinado S, Ignashkova TI, van Raam BJ, Baumann J, Sennott EL, Gendarme M, Lindemann RK, Starnbach MN, Reiling JH. TRAPPC13 modulates autophagy and the response to Golgi stress. J Cell Sci 2017; 130:2251-2265. [PMID: 28536105 DOI: 10.1242/jcs.199521] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 05/22/2017] [Indexed: 01/05/2023] Open
Abstract
Tether complexes play important roles in endocytic and exocytic trafficking of lipids and proteins. In yeast, the multisubunit transport protein particle (TRAPP) tether regulates endoplasmic reticulum (ER)-to-Golgi and intra-Golgi transport and is also implicated in autophagy. In addition, the TRAPP complex acts as a guanine nucleotide exchange factor (GEF) for Ypt1, which is homologous to human Rab1a and Rab1b. Here, we show that human TRAPPC13 and other TRAPP subunits are critically involved in the survival response to several Golgi-disrupting agents. Loss of TRAPPC13 partially preserves the secretory pathway and viability in response to brefeldin A, in a manner that is dependent on ARF1 and the large GEF GBF1, and concomitant with reduced caspase activation and ER stress marker induction. TRAPPC13 depletion reduces Rab1a and Rab1b activity, impairs autophagy and leads to increased infectivity to the pathogenic bacterium Shigella flexneri in response to brefeldin A. Thus, our results lend support for the existence of a mammalian TRAPPIII complex containing TRAPPC13, which is important for autophagic flux under certain stress conditions.
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Affiliation(s)
- Silvia Ramírez-Peinado
- Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany
| | - Tatiana I Ignashkova
- Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany
| | - Bram J van Raam
- Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany
| | - Jan Baumann
- Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany
| | - Erica L Sennott
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
| | - Mathieu Gendarme
- Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany
| | - Ralph K Lindemann
- Merck Serono TA Oncology, Merck KGaA, Frankfurter Str. 250, Darmstadt D-64293, Germany
| | - Michael N Starnbach
- Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA
| | - Jan H Reiling
- Metabolism and Signaling in Cancer, BioMed X Innovation Center, Im Neuenheimer Feld 583, Heidelberg 69120, Germany
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32
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Niklaus M, Adams O, Berezowska S, Zlobec I, Graber F, Slotta-Huspenina J, Nitsche U, Rosenberg R, Tschan MP, Langer R. Expression analysis of LC3B and p62 indicates intact activated autophagy is associated with an unfavorable prognosis in colon cancer. Oncotarget 2017; 8:54604-54615. [PMID: 28903368 PMCID: PMC5589607 DOI: 10.18632/oncotarget.17554] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Accepted: 03/24/2017] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a lysosomal degradation and recycling process implicated in cancer progression and therapy resistance. We assessed the impact of basal autophagy in colon cancer (CC) in vitro and ex vivo. Functional autophagy was demonstrated in CC cell lines (LoVo; HT-29) showing a dose-dependent increase of the autophagy markers LC3B, p62 and autophagic vesciles upon increasing concentrations of the autophagy inhibitor chloroquine, which was demonstrated by immunoblotting, immunofluorescence and electron microscopy. Next, tissue microarrays with 292 primary resected CC, with cores from different tumor regions, and normal mucosa were analyzed by immunohistochemistry for LC3B and p62. CC tissue showed LC3B dot-like, p62 dot-like, cytoplasmic and nuclear staining in various levels without significant intratumoral heterogeneity. Tumoral LC3B and p62 expression was significantly higher than in normal tissue (p<0.001). No associations between staining patterns and pathological features (e.g. TNM categories; grading) were observed. Both low LC3B dot-like and low p62 dot-like-cytoplasmic staining were associated with worse overall survival (p=0.005 and p=0.002). The best prognostic discrimination, however, was seen for a combination of LC3B dot-like/p62 dot-like-cytoplasmic staining: high expression of both markers, indicative of impaired activated autophagy, was associated with the best overall survival. In contrast, high LC3B dot-like/low p62 dot-like-cytoplasmic expression, indicative of intact activated autophagy, was associated with the worst outcome (p<0.001 in univariate and HR=0.751; CI=0.607-0.928; p=0.008 in multivariate analysis). These specific expression patterns of LC3B and p62 pointing to different states of autophagy associated with diverging clinical outcomes highlighte the potential significance of basal autophagy in CC biology.
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Affiliation(s)
- Monique Niklaus
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland
| | - Olivia Adams
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3008 Bern, Switzerland
| | - Sabina Berezowska
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland
| | - Inti Zlobec
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3008 Bern, Switzerland
| | - Franziska Graber
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland
| | | | - Ulrich Nitsche
- Department of Surgery, Technische Universität München, D-81675 München, Germany
| | - Robert Rosenberg
- Department of Surgery, Kantonsspital Liestal, CH-4410 Liestal, Switzerland
| | - Mario P Tschan
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland.,Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3008 Bern, Switzerland
| | - Rupert Langer
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland
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33
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Role of p62 in the suppression of inflammatory cytokine production by adiponectin in macrophages: Involvement of autophagy and p21/Nrf2 axis. Sci Rep 2017; 7:393. [PMID: 28341848 PMCID: PMC5428427 DOI: 10.1038/s41598-017-00456-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 02/27/2017] [Indexed: 02/08/2023] Open
Abstract
Adiponectin possesses potent anti-inflammatory properties. p62, an adaptor protein composed of multi-functional domain, is known to play a role in controlling inflammatory responses. In the present study, we examined the role of p62 in suppressing inflammatory cytokines produced by globular adiponectin (gAcrp) and the potential underlying mechanisms in macrophages. We demonstrated that gAcrp significantly increased p62 expression. Knockdown of p62 abrogated the suppressive effects of gAcrp on LPS-stimulated TNF-α and IL-1β expression and TRAF6/p38 MAPK pathway, indicating that p62 signaling is critical for suppressing inflammatory cytokines production by gAcrp. We next examined the role of p62 in gAcrp-induced autophagy activation, because autophagy has been shown to play a pivotal role in suppressing TNF-α. Herein, we observed that gene silencing of p62 prevented gAcrp-induced increases in autophagy-related genes and autophagosome formation. In addition, we found that Nrf2 knockdown prevented gAcrp-induced p62 expression, and p21 knockdown prevented Nrf2 induction, suggesting the role of p21/Nrf2 axis in gAcrp-induced p62 expression. Taken together, these findings imply that p62 signaling plays a crucial role in suppressing inflammatory cytokine production by globular adiponectin in macrophages, at least in part, through autophagy induction. Furthermore, the p21/Nrf2 signaling cascade contributes to p62 induction by globular adiponectin.
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Mokarram P, Albokashy M, Zarghooni M, Moosavi MA, Sepehri Z, Chen QM, Hudecki A, Sargazi A, Alizadeh J, Moghadam AR, Hashemi M, Movassagh H, Klonisch T, Owji AA, Łos MJ, Ghavami S. New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets. Autophagy 2017; 13:781-819. [PMID: 28358273 PMCID: PMC5446063 DOI: 10.1080/15548627.2017.1290751] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.
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Affiliation(s)
- Pooneh Mokarram
- a Colorectal Research Center and Department of Biochemistry , School of Medicine, Shiraz University of Medical Sciences , Shiraz , Iran
| | - Mohammed Albokashy
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Maryam Zarghooni
- c Zabol University of Medical Sciences , Zabol , Iran.,d University of Toronto Alumni , Toronto , ON , Canada
| | - Mohammad Amin Moosavi
- e Department of Molecular Medicine , Institute of Medical Biotechnology, National Institute for Genetic Engineering and Biotechnology , Tehran , Iran
| | - Zahra Sepehri
- c Zabol University of Medical Sciences , Zabol , Iran
| | - Qi Min Chen
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | | | | | - Javad Alizadeh
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Adel Rezaei Moghadam
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Mohammad Hashemi
- g Department of Clinical Biochemistry , School of Medicine, Zahedan University of Medical Sciences , Zahedan , Iran
| | - Hesam Movassagh
- h Department of Immunology , Rady Faculty of Health Sciences, College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Thomas Klonisch
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada
| | - Ali Akbar Owji
- i Department of Clinical Biochemistry , School of Medicine, Shiraz Medical University , Shiraz , Iran
| | - Marek J Łos
- j Małopolska Centre of Biotechnology , Jagiellonian University , Krakow , Poland ; LinkoCare Life Sciences AB , Sweden
| | - Saeid Ghavami
- b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada.,k Health Policy Research Center , Shiraz University of Medical Sciences , Shiraz , Iran
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Kosumi K, Masugi Y, Yang J, Qian ZR, Kim SA, Li W, Shi Y, da Silva A, Hamada T, Liu L, Gu M, Twombly TS, Cao Y, Barbie DA, Nosho K, Baba H, Garrett WS, Meyerhardt JA, Giovannucci EL, Chan AT, Fuchs CS, Ogino S, Nishihara R. Tumor SQSTM1 (p62) expression and T cells in colorectal cancer. Oncoimmunology 2017; 6:e1284720. [PMID: 28405513 DOI: 10.1080/2162402x.2017.1284720] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 01/12/2017] [Accepted: 01/13/2017] [Indexed: 12/15/2022] Open
Abstract
Evidence suggests that activation of autophagy in neoplastic cells potentiates antitumor immunity through cross-presentation of tumor-associated antigens to T cells and release of immune mediators. The SQSTM1 (sequestosome 1, p62) protein is degraded by activated autophagy, and might enhance immune response to tumor cells. We hypothesized that tumor SQSTM1 expression level might be inversely associated with T-cell densities in colorectal carcinoma tissue. We evaluated tumor SQSTM1 expression by immunohistochemistry in 601 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. Ordinal logistic regression analyses were conducted to assess the association of tumor SQSTM1 expression with CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+ cell density in tumor tissue, controlling for potential confounders, including tumor status of microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, and KRAS, BRAF, and PIK3CA mutations. Tumor SQSTM1 expression level was inversely associated with FOXP3+ cell density (ptrend = 0.006), but not with CD3+, CD8+, or CD45RO+ cell density (with the adjusted α level of 0.01 for multiple hypothesis testing). For a unit increase in quartile categories of FOXP3+ cell density, multivariable odds ratios were 0.66 [95% confidence interval (CI), 0.45-0.98] for intermediate-level SQSTM1 expression, and 0.55 (95% CI, 0.36-0.83) for high-level SQSTM1 expression, compared with low-level SQSTM1 expression. Tumor SQSTM1 expression is inversely associated with FOXP3+ cell density in colorectal cancer tissue, suggesting a possible role of SQSTM1-expressing carcinoma cells on regulatory T cells in the tumor microenvironment.
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Affiliation(s)
- Keisuke Kosumi
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Yohei Masugi
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Juhong Yang
- Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University , Tianjin, China
| | - Zhi Rong Qian
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Sun A Kim
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health , Bethesda, MD, USA
| | - Wanwan Li
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Yan Shi
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Annacarolina da Silva
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Tsuyoshi Hamada
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Li Liu
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Mancang Gu
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Tyler S Twombly
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Yin Cao
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - David A Barbie
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Katsuhiko Nosho
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine , Sapporo, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University , Kumamoto, Japan
| | - Wendy S Garrett
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Jeffery A Meyerhardt
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School , Boston, MA, USA
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Charles S Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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36
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Zhou H, Yuan M, Yu Q, Zhou X, Min W, Gao D. Autophagy regulation and its role in gastric cancer and colorectal cancer. Cancer Biomark 2017; 17:1-10. [PMID: 27314289 DOI: 10.3233/cbm-160613] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Autophagy is associated with the occurrence, development, cellular adaptation, progression, treatment and prognosis of gastric cancer (GC) and colorectal cancer (CRC). The effect of autophagy in these two cancers has attracted our attention. OBJECTIVE The aim of this study was to describe the functional and regulatory mechanisms associated with autophagy in GC and CRC. METHODS We reviewed recent publications describing the role of autophagy in GC and CRC, including the functional characteristics, clinical significance and regulatory mechanisms. RESULTS Autophagy plays context-dependent dual roles in the development and progression of GC and CRC. It can either promote tumor growth and cell survival or can contribute to tumor suppression and promote cell death. Both of these effects employ complex regulatory networks, such as those mediated by p53, PI3K/Akt/mTOR, Ras and microRNA. Among the cellular process associated with these pathways, autophagy is a potential target for anti-tumor therapy. CONCLUSION Autophagy is associated with both tumorigenic and protective effects in cancer. However, the role of autophagy in GC and CRC remains unclear. Although the translation of the basic science of autophagy into clinical practice is a long process, the modulation of autophagy as a potential therapeutic approach in GC and CRC merits further investigation.
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Affiliation(s)
- Huangyan Zhou
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi, China.,Jiangxi Academy of Medical Sciences, Nanchang, Jiangxi, China.,Institute of Immunotherapy, Nanchang University, Nanchang, Jiangxi, China
| | - Min Yuan
- Department of Neurology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qiongfang Yu
- Department of Gastroenterology and Hepatology, Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Xiaoyan Zhou
- Department of Pathophysiology, Medical College of Nanchang University, Nanchang, Jiangxi, China
| | - Weiping Min
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi, China.,Jiangxi Academy of Medical Sciences, Nanchang, Jiangxi, China.,Institute of Immunotherapy, Nanchang University, Nanchang, Jiangxi, China
| | - Dian Gao
- Department of Pathogen Biology and Immunology, Medical College of Nanchang University, Nanchang, Jiangxi, China.,Jiangxi Academy of Medical Sciences, Nanchang, Jiangxi, China.,Institute of Immunotherapy, Nanchang University, Nanchang, Jiangxi, China
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37
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Huang H, Zhu J, Li Y, Zhang L, Gu J, Xie Q, Jin H, Che X, Li J, Huang C, Chen LC, Lyu J, Gao J, Huang C. Upregulation of SQSTM1/p62 contributes to nickel-induced malignant transformation of human bronchial epithelial cells. Autophagy 2016; 12:1687-1703. [PMID: 27467530 PMCID: PMC5079680 DOI: 10.1080/15548627.2016.1196313] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Chronic lung inflammation is accepted as being associated with the development of lung cancer caused by nickel exposure. Therefore, identifying the molecular mechanisms that lead to a nickel-induced sustained inflammatory microenvironment that causes transformation of human bronchial epithelial cells is of high significance. In the current studies, we identified SQSTM1/p62 as a novel nickel-upregulated protein that is important for nickel-induced inflammatory TNF expression, subsequently resulting in transformation of human bronchial epithelial cells. We found that nickel exposure induced SQSTM1 protein upregulation in human lung epithelial cells in vitro and in mouse lung tissues in vivo. The SQSTM1 upregulation was also observed in human lung squamous cell carcinoma. Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation. Mechanistic studies showed that the SQSTM1 upregulation by nickel was the compromised result of upregulating SQSTM1 mRNA transcription and promoting SQSTM1 protein degradation. We demonstrated that nickel-initiated SQSTM1 protein degradation is mediated by macroautophagy/autophagy via an MTOR-ULK1-BECN1 axis, whereas RELA is important for SQSTM1 transcriptional upregulation following nickel exposure. Furthermore, SQSTM1 upregulation exhibited its promotion of nickel-induced cell transformation through exerting an impetus for nickel-induced inflammatory TNF mRNA stability. Consistently, the MTOR-ULK1-BECN1 autophagic cascade acted as an inhibitory effect on nickel-induced TNF expression and cell transformation. Collectively, our results demonstrate a novel SQSTM1 regulatory network that promotes a nickel-induced tumorigenic effect in human bronchial epithelial cells, which is negatively controlled by an autophagic cascade following nickel exposure.
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Affiliation(s)
- Haishan Huang
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.,b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
| | - Junlan Zhu
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.,b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
| | - Yang Li
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.,b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
| | - Liping Zhang
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Jiayan Gu
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Qipeng Xie
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Honglei Jin
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.,b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
| | - Xun Che
- b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
| | - Jingxia Li
- b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
| | - Chao Huang
- b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
| | - Lung-Chi Chen
- b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
| | - Jianxin Lyu
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Jimin Gao
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China
| | - Chuanshu Huang
- a Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University , Wenzhou , Zhejiang , China.,b Nelson Institute of Environmental Medicine, New York University School of Medicine , Tuxedo , NY , USA
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38
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Zaytseva YY, Harris JW, Mitov MI, Kim JT, Butterfield DA, Lee EY, Weiss HL, Gao T, Evers BM. Increased expression of fatty acid synthase provides a survival advantage to colorectal cancer cells via upregulation of cellular respiration. Oncotarget 2016; 6:18891-904. [PMID: 25970773 PMCID: PMC4662462 DOI: 10.18632/oncotarget.3783] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 04/06/2015] [Indexed: 12/25/2022] Open
Abstract
Fatty acid synthase (FASN), a lipogenic enzyme, is upregulated in colorectal cancer (CRC). Increased de novo lipid synthesis is thought to be a metabolic adaptation of cancer cells that promotes survival and metastasis; however, the mechanisms for this phenomenon are not fully understood. We show that FASN plays a role in regulation of energy homeostasis by enhancing cellular respiration in CRC. We demonstrate that endogenously synthesized lipids fuel fatty acid oxidation, particularly during metabolic stress, and maintain energy homeostasis. Increased FASN expression is associated with a decrease in activation of energy-sensing pathways and accumulation of lipid droplets in CRC cells and orthotopic CRCs. Immunohistochemical evaluation demonstrated increased expression of FASN and p62, a marker of autophagy inhibition, in primary CRCs and liver metastases compared to matched normal colonic mucosa. Our findings indicate that overexpression of FASN plays a crucial role in maintaining energy homeostasis in CRC via increased oxidation of endogenously synthesized lipids. Importantly, activation of fatty acid oxidation and consequent downregulation of stress-response signaling pathways may be key adaptation mechanisms that mediate the effects of FASN on cancer cell survival and metastasis, providing a strong rationale for targeting this pathway in advanced CRC.
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Affiliation(s)
| | - Jennifer W Harris
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.,Department of Surgery, University of Kentucky, Lexington, Kentucky, USA
| | - Mihail I Mitov
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Ji Tae Kim
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - D Allan Butterfield
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.,Department of Chemistry, University of Kentucky, Lexington, Kentucky, USA
| | - Eun Y Lee
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.,Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky, USA
| | - Heidi L Weiss
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - Tianyan Gao
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA
| | - B Mark Evers
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.,Department of Surgery, University of Kentucky, Lexington, Kentucky, USA
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39
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Zhang J, Yang Z, Dong J. P62: An emerging oncotarget for osteolytic metastasis. J Bone Oncol 2016; 5:30-7. [PMID: 26998424 PMCID: PMC4782024 DOI: 10.1016/j.jbo.2016.01.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 01/18/2016] [Accepted: 01/30/2016] [Indexed: 12/13/2022] Open
Abstract
Bone metastasis occurs in the majority of late-stage tumors with poor prognosis. It is mainly classified as osteoblastic metastasis and osteolytic metastasis. The pathogenesis of osteolytic metastasis is a “vicious cycle” between tumor cells and bone cells (primarily the osteoclasts), which is mediated by secretory factors. The P62 adapter protein is a versatile multitasker between tumor cells and bone cells. The overexpression of P62 has been detected among a variety of tumors, playing positive roles in both tumorigenesis and metastasis. Moreover, P62 is an important modulator of the osteoclastogenesis pathway. Therefore, the ability of P62 to modulate tumors and osteoclasts suggests that it may be a feasible oncotarget for bone metastasis, especially for osteolytic metastasis. Recent research has shown that a P62 DNA vaccine triggered effective anti-tumor, anti-metastatic and anti-osteoporotic activities. Growing lines of evidence point to P62 as an emerging oncotarget for osteolytic metastasis. In this review, we outline the different roles of P62 in tumor cells and osteoclasts, focusing on the P62-related signaling pathway in key steps of osteolytic metastasis, including tumorigenesis, metastasis and osteoclastogenesis. Finally, we discuss the newest observations on P62 as an oncotarget for osteolytic metastasis treatment.
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Affiliation(s)
- Jing Zhang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan 650118, PR China
| | - Zuozhang Yang
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan 650118, PR China
| | - Jian Dong
- Bone and Soft Tissue Tumors Research Center of Yunnan Province, Department of Orthopaedics, The Third Affiliated Hospital of Kunming Medical University, Tumor Hospital of Yunnan Province, Kunming, Yunnan 650118, PR China; Stem Cell Therapy Technical of Clinical Transformation and Basic Research Key Laboratory of Yunnan Province, Kunming, Yunnan 650118, PR China
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40
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Burada F, Nicoli ER, Ciurea ME, Uscatu DC, Ioana M, Gheonea DI. Autophagy in colorectal cancer: An important switch from physiology to pathology. World J Gastrointest Oncol 2015; 7:271-284. [PMID: 26600927 PMCID: PMC4644850 DOI: 10.4251/wjgo.v7.i11.271] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 06/20/2015] [Accepted: 09/30/2015] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of autophagy-related genes and modulators in colorectal carcinogenesis, and to develop potential beneficial agents for the prognosis and treatment of CRC.
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41
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Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, Kemp AJ, Nookala RK, Blenis J, Coull BJ, Murray JT, van Steensel MA, Wilkinson S, Tee AR. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy 2014; 10:1749-60. [PMID: 25126726 PMCID: PMC4198360 DOI: 10.4161/auto.29640] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Birt-Hogg-Dubé (BHD) syndrome is a rare autosomal dominant condition caused by mutations in the FLCN gene and characterized by benign hair follicle tumors, pneumothorax, and renal cancer. Folliculin (FLCN), the protein product of the FLCN gene, is a poorly characterized tumor suppressor protein, currently linked to multiple cellular pathways. Autophagy maintains cellular homeostasis by removing damaged organelles and macromolecules. Although the autophagy kinase ULK1 drives autophagy, the underlying mechanisms are still being unraveled and few ULK1 substrates have been identified to date. Here, we identify that loss of FLCN moderately impairs basal autophagic flux, while re-expression of FLCN rescues autophagy. We reveal that the FLCN complex is regulated by ULK1 and elucidate 3 novel phosphorylation sites (Ser406, Ser537, and Ser542) within FLCN, which are induced by ULK1 overexpression. In addition, our findings demonstrate that FLCN interacts with a second integral component of the autophagy machinery, GABA(A) receptor-associated protein (GABARAP). The FLCN-GABARAP association is modulated by the presence of either folliculin-interacting protein (FNIP)-1 or FNIP2 and further regulated by ULK1. As observed by elevation of GABARAP, sequestome 1 (SQSTM1) and microtubule-associated protein 1 light chain 3 (MAP1LC3B) in chromophobe and clear cell tumors from a BHD patient, we found that autophagy is impaired in BHD-associated renal tumors. Consequently, this work reveals a novel facet of autophagy regulation by ULK1 and substantially contributes to our understanding of FLCN function by linking it directly to autophagy through GABARAP and ULK1.
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Affiliation(s)
- Elaine A Dunlop
- Institute of Cancer and Genetics, Cardiff University; Heath Park, Cardiff, Wales UK
| | - Sara Seifan
- Institute of Cancer and Genetics, Cardiff University; Heath Park, Cardiff, Wales UK
| | - Tijs Claessens
- Institute of Cancer and Genetics, Cardiff University; Heath Park, Cardiff, Wales UK; Department of Dermatology; GROW School for Oncology and Developmental Biology; Maastricht University Medical Center; Maastricht, Netherlands
| | - Christian Behrends
- Frankfurt Institute for Molecular Life Sciences (FMLS) and Institute of Biochemistry II; Goethe University School of Medicine; Frankfurt, Germany
| | - Miriam Af Kamps
- Department of Dermatology; GROW School for Oncology and Developmental Biology; Maastricht University Medical Center; Maastricht, Netherlands
| | - Ewelina Rozycka
- Centre for Cancer Research and Cell Biology; School of Medicine, Dentistry and Biomedical Science; Queen's University Belfast; Belfast, UK
| | - Alain J Kemp
- Institute of Genetics and Molecular Medicine; Edinburgh Cancer Research UK Centre; University of Edinburgh; Edinburgh, UK
| | - Ravi K Nookala
- Department of Biochemistry; University of Cambridge; Cambridge, UK
| | - John Blenis
- Department of Cell Biology; Harvard Medical School; Boston, MA USA
| | - Barry J Coull
- Department of Dermatology; GROW School for Oncology and Developmental Biology; Maastricht University Medical Center; Maastricht, Netherlands
| | - James T Murray
- Centre for Cancer Research and Cell Biology; School of Medicine, Dentistry and Biomedical Science; Queen's University Belfast; Belfast, UK; Trinity Biomedical Sciences Institute; School of Biochemistry and Immunology; Trinity College; Dublin, Ireland
| | - Maurice Am van Steensel
- Department of Dermatology; GROW School for Oncology and Developmental Biology; Maastricht University Medical Center; Maastricht, Netherlands; Immunos; Institute of Medical Biology; Singapore
| | - Simon Wilkinson
- Institute of Genetics and Molecular Medicine; Edinburgh Cancer Research UK Centre; University of Edinburgh; Edinburgh, UK
| | - Andrew R Tee
- Institute of Cancer and Genetics, Cardiff University; Heath Park, Cardiff, Wales UK
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Zhang L, Sung JJY, Yu J, Ng SC, Wong SH, Cho CH, Ng SSM, Chan FKL, Wu WKK. Xenophagy in Helicobacter pylori- and Epstein-Barr virus-induced gastric cancer. J Pathol 2014; 233:103-12. [PMID: 24633785 DOI: 10.1002/path.4351] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 02/27/2014] [Accepted: 03/07/2014] [Indexed: 12/12/2022]
Abstract
Helicobacter pylori and Epstein-Barr virus (EBV) account for roughly 80% and 10%, respectively, of gastric carcinomas worldwide. Autophagy is an evolutionarily conserved and intricately regulated cellular process that involves the sequestration of cytoplasmic proteins and organelles into double-membrane autophagosomes that eventually fuse with lysosomes for degradation of the engulfed content. Emerging evidence indicates that xenophagy, a form of selective autophagy, plays a crucial role in the pathogenesis of H. pylori- and EBV-induced gastric cancer. Xenophagy specifically recognizes intracellular H. pylori and EBV and physically targets these pathogens to the autophagosomal-lysosomal pathway for degradation. In this connection, H. pylori or EBV-induced dysregulation of autophagy may be causally linked to gastric tumourigenesis and therefore can be exploited as therapeutic targets. This review will discuss how H. pylori and EBV infection activate autophagy and how these pathogens evade recognition and degradation by the autophagic pathway. Elucidating the molecular aspects of H. pylori- and EBV-induced autophagy will help us better understand the pathogenesis of gastric cancer and promote the development of autophagy modulators as antimicrobial agents.
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Affiliation(s)
- Lin Zhang
- Institute of Digestive Diseases and State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong, China
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Prognostic significance of p62/SQSTM1 subcellular localization and LC3B in oral squamous cell carcinoma. Br J Cancer 2014; 111:944-54. [PMID: 24983366 PMCID: PMC4150268 DOI: 10.1038/bjc.2014.355] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Revised: 05/05/2014] [Accepted: 05/30/2014] [Indexed: 12/19/2022] Open
Abstract
Background: Autophagy is a programmed cell survival mechanism that has a key role in both physiologic and pathologic conditions. The relationship between autophagy and cancer is complex because autophagy can act as either a tumour suppressor or as a tumour promoter. The role of autophagy in oral squamous cell carcinoma (OSCC) is controversial. Several studies have claimed that either a high or low expression of autophagy-related proteins was associated with poor prognosis of OSCCs. The aims of the study were to compare autophagy in OSCCs, verrucous hyperplasias, and normal oral mucosas, and to inspect the prognostic role of autophagy in OSCCs. Methods: We used the autophagosome marker, LC3B, and autophagy flux marker, p62/SQSTM1 (p62), by using immunohistochemistry, and examined p62 mRNA by RNA in situ hybridization, to evaluate autophagy in 195 OSCCs, 47 verrucous hyperplasias, and 37 normal oral mucosas. The prognostic roles of LC3B and p62 protein expressions in OSCCs were investigated. Results: We discovered that the normal oral mucosa exhibited limited LC3B punctae and weak cytoplasmic p62 staining, whereas the OSCCs exhibited a marked increase in LC3B punctae and cytoplasmic p62 expression. The expression pattern of LC3B and cytoplasmic p62 of the verrucous hyperplasias were between normal oral mucosas and OSCCs. The normal oral mucosas, verrucous hyperplasias, and OSCCs presented no differences in nuclear p62 expression and the p62 mRNA level. p62 mRNA expression was elevated in a minority of cases. High p62 mRNA expression was associated with high p62 protein expression in the cytoplasm. Increased LC3B punctae, high cytoplasmic p62, and low nuclear p62 expressions in OSCCs were associated with aggressive clinicopathologic features and unfavourable prognosis. In addition, low nuclear p62 expression was an independent prognostic factor for overall and disease-specific survival rates. Furthermore, we disclosed that high cytoplasmic p62 expression accompanied with either a low or high LC3B expression, which indicated autophagy impairment under basal or activated autophagic activity, was associated with aggressive behaviour in advanced OSCCs. Conclusions: We suggested that autophagy was altered during cancer initiation and progression. Autophagy impairment contributed to cancer progression in advanced OSCCs.
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Vallejo D, Crespo I, San-Miguel B, Alvarez M, Prieto J, Tuñón MJ, González-Gallego J. Autophagic response in the Rabbit Hemorrhagic Disease, an animal model of virally-induced fulminant hepatic failure. Vet Res 2014; 45:15. [PMID: 24490870 PMCID: PMC3922607 DOI: 10.1186/1297-9716-45-15] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Accepted: 01/22/2014] [Indexed: 01/05/2023] Open
Abstract
The Rabbit Hemorrhagic Disease Virus (RHDV) induces a severe disease that fulfils many requirements of an animal model of fulminant hepatic failure. However, a better knowledge of molecular mechanisms contributing to liver damage is required, and it is unknown whether the RHDV induces liver autophagy and how it relates to apoptosis. In this study, we attempted to explore which signalling pathways were involved in the autophagic response induced by the RHDV and to characterize their role in the context of RHDV pathogenesis. Rabbits were infected with 2 × 10⁴ hemmaglutination units of a RHDV isolate. The autophagic response was measured as presence of autophagic vesicles, LC3 staining, conversion of LC3-I to autophagosome-associated LC3-II and changes in expression of beclin-1, UVRAG, Atg5, Atg12, Atg16L1 and p62/SQSTM1. RHDV-triggered autophagy reached a maximum at 24 hours post-infection (hpi) and declined at 30 and 36 hpi. Phosphorylation of mTOR also augmented in early periods of infection and there was an increase in the expression of the endoplasmic reticulum chaperones BiP/GRP78, CHOP and GRP94. Apoptosis, measured as caspase-3 activity and expression of PARP-1, increased significantly at 30 and 36 hpi in parallel to the maximal expression of the RHDV capsid protein VP60. These data indicate that RHDV infection initiates a rapid autophagic response, perhaps in an attempt to protect liver, which associates to ER stress development and is independent from downregulation of the major autophagy suppressor mTOR. As the infection continues and the autophagic response declines, cells begin to exhibit apoptosis.
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Affiliation(s)
| | | | | | | | | | - María Jesús Tuñón
- Institute of Biomedicine (IBIOMED), University of León, 24071 León, Spain.
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Samarasinghe B, Wales CTK, Taylor FR, Jacobs AT. Heat shock factor 1 confers resistance to Hsp90 inhibitors through p62/SQSTM1 expression and promotion of autophagic flux. Biochem Pharmacol 2013; 87:445-55. [PMID: 24291777 DOI: 10.1016/j.bcp.2013.11.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 11/18/2013] [Indexed: 02/06/2023]
Abstract
Heat shock protein 90 (Hsp90) has an important role in many cancers. Biochemical inhibitors of Hsp90 are in advanced clinical development for the treatment of solid and hematological malignancies. At the cellular level, their efficacy is diminished by the fact that Hsp90 inhibition causes activation of heat shock factor 1 (HSF1). We report a mechanism by which HSF1 activation diminishes the effect of Hsp90 inhibitors geldanamycin and 17-allylaminogeldanamycin (17-AAG, tanespimycin). Silencing HSF1 with siRNA or inhibiting HSF1 activity with KRIBB11 lowers the threshold for apoptosis in geldanamycin and 17-AAG-treated cancer cells. Autophagy also mitigates the actions of Hsp90 inhibitors. Blocking autophagy with 3-methyladenine (3-MA), bafilomycin A1, or beclin 1 siRNA also lower the threshold for apoptosis. Exploring a potential relationship between HSF1 and autophagy, we monitored autophagosome formation and autophagic flux in control and HSF1-silenced cells. Results show HSF1 is required for autophagy in Hsp90 inhibitor-treated cells. The reduced autophagy observed in HSF1-silenced cells correlates with enhanced cell death. To investigate how HSF1 promotes autophagy, we monitored the expression of genes involved in the autophagic cascade. These data show that sequestosome 1 (p62/SQSTM1), a protein involved in the delivery of autophagic substrates and nucleation of autophagosomes, is an HSF1-regulated gene. Gene silencing was used to evaluate the significance of p62/SQSTM1 in Hsp90 inhibitor resistance. Cells where p62/SQSTM1 was silenced showed a dramatic increase in sensitivity to Hsp90 inhibitors. Results highlight the importance of HSF1 and HSF1-dependent p62/SQSTM1 expression in resistance Hsp90 inhibitors, underscoring the potential of targeting HSF1 to improve the efficacy of Hsp90 inhibitors in cancer.
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Affiliation(s)
- Buddhini Samarasinghe
- Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili St., Hilo, HI 96720, United States
| | - Christina T K Wales
- Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili St., Hilo, HI 96720, United States
| | - Frederick R Taylor
- Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili St., Hilo, HI 96720, United States
| | - Aaron T Jacobs
- Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 W. Kawili St., Hilo, HI 96720, United States; University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, HI 96813, United States.
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