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Ivanova T, Sbirkov Y, Kazakova M, Sarafian V. Lysosomes and LAMPs as Autophagy Drivers of Drug Resistance in Colorectal Cancer. Cells 2025; 14:574. [PMID: 40277899 PMCID: PMC12025563 DOI: 10.3390/cells14080574] [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: 02/16/2025] [Revised: 04/04/2025] [Accepted: 04/08/2025] [Indexed: 04/26/2025] Open
Abstract
Colorectal cancer (CRC) is among the most malignant pathologies worldwide. A major factor contributing to the poor prognosis of neoplastic diseases is the development of drug resistance. It significantly reduces the utility of most therapeutic protocols and necessitates the search for novel biomarkers and treatment strategies to combat cancer. An evolutionarily conserved catabolic mechanism, autophagy maintains nutrient recycling and metabolic adaptation and is also closely related to carcinogenesis, playing a dual role. Autophagy inhibition can limit the growth of tumors and improve the response to cancer therapeutics. Lysosomes, key players in autophagy, are also considered promising targets for anticancer treatment. There are still insufficient data on the role of poorly studied glycoproteins related to autophagy, such as the lysosome-associated membrane glycoproteins (LAMPs). They can act as multifunctional molecules involved in a multitude of processes like autophagy and cancer development. In the current review, we summarize the recent data on the double-faceted role of autophagy in cancer with a focus on drug resistance in CRC and on the roles of lysosomes and LAMPs in these interconnected processes. Several lysosomotropic drugs are discussed as options to overcome cancer cell chemoresistance. The complex networks that underline defined autophagic pathways in the context of CRC carcinogenesis and the role of autophagy, especially of LAMPs as drivers of drug resistance, are outlined.
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Affiliation(s)
- Tsvetomira Ivanova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Yordan Sbirkov
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Maria Kazakova
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
| | - Victoria Sarafian
- Department of Medical Biology, Medical University-Plovdiv, 4000 Plovdiv, Bulgaria; (Y.S.); (M.K.)
- Research Division of Molecular and Regenerative Medicine, Research Institute at Medical University-Plovdiv, 4000 Plovdiv, Bulgaria
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Yang Y, Li Y, Wang Y, Chen X, Yao Y, Li D, Yu G, Song X. The role and regulatory mechanism of lysosome associated protein transmembrane 4β in tumors. Front Oncol 2025; 15:1552007. [PMID: 40231269 PMCID: PMC11995161 DOI: 10.3389/fonc.2025.1552007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 03/12/2025] [Indexed: 04/16/2025] Open
Abstract
The oncogene LAPTM4B (encoding lysosome-associated protein transmembrane-4β), first cloned in hepatocellular carcinoma cells, is located on chromosome 8q22.1 and encodes two isoforms, LAPTM4B-35 and LAPTM4B-24. LAPTM4B proteins have four transmembrane structural domains and are mainly distributed in lysosomal and endosomal membranes of cells. Studies have shown that LAPTM4B is overexpressed in a variety of cancers, in which the genetic polymorphism of LAPTM4B is associated with tumor susceptibility. LAPTM4B also regulates various cell signaling pathways, interacts with autophagy-related proteins and ceramides, and regulates the autophagy process and the release of exosomes, which in turn affect the survival and drug resistance of tumor cells. In conclusion, this paper summarizes recent research on LAPTM4B, aiming to explore the role and potential mechanisms of LAPTM4B in a variety of tumors.
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Affiliation(s)
- Yuteng Yang
- The 2nd Medical College of Binzhou Medical University, Yantai, China
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Yumei Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Yaqi Wang
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Xi Chen
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Yisong Yao
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Dongxian Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Guohua Yu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, China
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Allen PE, Adcox HE, Siff TE, Gupta S, Hunt JR, Carlyon JA. Orientia tsutsugamushi alters the intranuclear balance of cullin-1 and c-MYC to inhibit apoptosis. Infect Immun 2025; 93:e0055924. [PMID: 39976440 PMCID: PMC11895443 DOI: 10.1128/iai.00559-24] [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: 12/03/2024] [Accepted: 01/23/2025] [Indexed: 02/21/2025] Open
Abstract
Cullin-1 (Cul1), a cullin-RING ubiquitin ligase component, represses c-MYC activity in the nucleus. Orientia tsutsugamushi causes the potentially fatal rickettsiosis, scrub typhus. The obligate intracellular bacterium encodes an arsenal of ankyrin repeat-containing effectors (Anks), many of which carry a eukaryotic-like F-box motif that binds Cul1. O. tsutsugamushi reduces Cul1 levels in the nucleus. This phenomenon is not due to an alteration in Cul1 neddylation but is bacterial burden- and protein synthesis-dependent. Five of the 11 Anks capable of binding Cul1 (Ank1, Ank5, Ank6, Ank9, Ank17) sequester it in the cytoplasm when each is ectopically expressed. Ank1 and Ank6 proteins with alanine substitutions in their F-boxes that render them unable to bind Cul1 cannot exclude Cul1 from the nucleus. Coincident with the reduction of Cul1 in the nuclei of Orientia-infected cells, c-MYC nuclear levels are elevated, and Cul1 target genes are differentially expressed. Several of these genes regulate apoptosis. The resistance of O. tsutsugamushi-infected cells to staurosporine-induced apoptosis is recapitulated in uninfected cells expressing Ank1 or Ank6 but not alanine-substituted versions thereof that cannot bind Cul1. Other F-box-containing Anks that cannot bind or exclude Cul1 from the nucleus also fail to confer resistance to apoptosis. Overall, O. tsutsugamushi modulates the Cul1:c-MYC intranuclear balance as an anti-apoptotic strategy that is functionally linked to a subset of its F-box-containing Anks.
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Affiliation(s)
- Paige E. Allen
- Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, Virginia, USA
| | - Haley E. Adcox
- Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, Virginia, USA
| | - Thomas E. Siff
- Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, Virginia, USA
| | - Sarika Gupta
- Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, Virginia, USA
| | - Jason R. Hunt
- Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, Virginia, USA
| | - Jason A. Carlyon
- Department of Microbiology and Immunology, Virginia Commonwealth University Medical Center, School of Medicine, Richmond, Virginia, USA
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Sobhani N, Pittacolo M, D’Angelo A, Marchegiani G. Recent Anti-KRAS G12D Therapies: A "Possible Impossibility" for Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2025; 17:704. [PMID: 40002297 PMCID: PMC11853620 DOI: 10.3390/cancers17040704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/13/2025] [Accepted: 02/16/2025] [Indexed: 02/27/2025] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown a dismal survival prognosis, resulting in less than a year of life in the metastatic setting. Methods: The pressing need to find better therapeutic methods brought about the discovery of new targeted therapies against the infamous KRAS mutations, the major oncological drivers of PDAC. Results: The most common KRAS mutation is KRASG12D, which causes a conformational change in the protein that constitutively activates downstream signaling pathways driving cancer hallmarks. Novel anti-KRASG12D therapies have been developed for solid-organ tumors, including small compounds, pan-RAS inhibitors, protease inhibitors, chimeric T cell receptors, and therapeutic vaccines. Conclusions: This comprehensive review summarizes current knowledge on the biology of KRAS-driven PDAC, the latest therapeutic options that have been experimentally validated, and developments in ongoing clinical trials.
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Affiliation(s)
- Navid Sobhani
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Matteo Pittacolo
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy;
| | - Alberto D’Angelo
- Department of Medicine, Northern General Hospital, Sheffield S5 7AT, UK;
| | - Giovanni Marchegiani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy;
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Shao S, Cui D, Zheng C, Xiong X, Zhao Y. WSB2 inhibits apoptosis and autophagy by targeting NOXA for degradation. MedComm (Beijing) 2025; 6:e70071. [PMID: 39866840 PMCID: PMC11758357 DOI: 10.1002/mco2.70071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 12/20/2024] [Accepted: 12/22/2024] [Indexed: 01/28/2025] Open
Affiliation(s)
- Shengpeng Shao
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhouChina
| | - Danrui Cui
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhouChina
| | - Chutian Zheng
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhouChina
| | - Xiufang Xiong
- Cancer Institute of the Second Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhouChina
| | - Yongchao Zhao
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhouChina
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Zhang J, Zhang J, Yang C. Autophagy in brain tumors: molecular mechanisms, challenges, and therapeutic opportunities. J Transl Med 2025; 23:52. [PMID: 39806481 PMCID: PMC11727735 DOI: 10.1186/s12967-024-06063-0] [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: 07/20/2024] [Accepted: 12/27/2024] [Indexed: 01/16/2025] Open
Abstract
Autophagy is responsible for maintaining cellular balance and ensuring survival. Autophagy plays a crucial role in the development of diseases, particularly human cancers, with actions that can either promote survival or induce cell death. However, brain tumors contribute to high levels of both mortality and morbidity globally, with resistance to treatments being acquired due to genetic mutations and dysregulation of molecular mechanisms, among other factors. Hence, having knowledge of the role of molecular processes in the advancement of brain tumors is enlightening, and the current review specifically examines the role of autophagy. The discussion would focus on the molecular pathways that control autophagy in brain tumors, and its dual role as a tumor suppressor and a supporter of tumor survival. Autophagy can control the advancement of different types of brain tumors like glioblastoma, glioma, and ependymoma, demonstrating its potential for treatment. Autophagy mechanisms can influence metastasis and drug resistance in glioblastoma, and there is a complex interplay between autophagy and cellular responses to stress like hypoxia and starvation. Autophagy can inhibit the growth of brain tumors by promoting apoptosis. Hence, focusing on autophagy could offer fresh perspectives on creating successful treatments.
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Affiliation(s)
- Jiarui Zhang
- Department of Pathology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jinan Zhang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, China.
| | - Chen Yang
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, No. 569 Xinsi Road, Xi'an, China.
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Xu C, Wen S, Du X, Zou X, Leung ELH, Zhou G, Wu Q, Shen B. Targeting regulated cell death (RCD) with naturally derived sesquiterpene lactones in cancer therapy. Pharmacol Res 2025; 211:107553. [PMID: 39706282 DOI: 10.1016/j.phrs.2024.107553] [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: 09/30/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 12/23/2024]
Abstract
Regulated cell death (RCD) is a type of cell death modulated by specific signal transduction pathways. Currently, known RCD types include apoptosis, autophagy, ferroptosis, necroptosis, cuproptosis, pyroptosis, and NETosis. Mutations in cancer cells may prevent the RCD pathway; therefore, targeting RCD in tumors has become a promising therapeutic approach. Sesquiterpene lactones represent a diverse and extensive class of plant-derived phytochemicals that serve as potential sources for developing various drugs. Recent studies have shown that sesquiterpene lactones have promising potential in cancer treatment. This review systematically summarizes recent progress in the study of sesquiterpene lactones as antitumor agents, highlighting their role in targeting various RCD pathways, including those involved in apoptosis, autophagy, ferroptosis, necroptosis, and cuproptosis. The primary purpose of the present review is to provide a clear picture of the regulation of RCD by sesquiterpene lactones against different targets in various cancers, which will facilitate the development of new strategies for cancer therapy.
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Affiliation(s)
- Cong Xu
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China; State Key Laboratory of Quality Research in Chinese Medicines and Faculty of Chinese Medicine, Macau University of Science and Technology, 999078, Macao
| | - Shaodi Wen
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China
| | - Xiaoyue Du
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China
| | - Xinhua Zou
- Department of Vascular and Tumor Interventional Medicine, Affiliated Hospital of Jining Medical University, Jining 272000, China
| | | | - Guoren Zhou
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China
| | - Qibiao Wu
- State Key Laboratory of Quality Research in Chinese Medicines and Faculty of Chinese Medicine, Macau University of Science and Technology, 999078, Macao.
| | - Bo Shen
- Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing 210000, China; DongTai People's Hospital, Dongtai, Jiangsu, China.
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Rajendran D, Oon CE. Navigating therapeutic prospects by modulating autophagy in colorectal cancer. Life Sci 2024; 358:123121. [PMID: 39389340 DOI: 10.1016/j.lfs.2024.123121] [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: 06/13/2024] [Revised: 09/25/2024] [Accepted: 10/05/2024] [Indexed: 10/12/2024]
Abstract
Colorectal cancer (CRC) remains a leading cause of death globally despite the improvements in cancer treatment. Autophagy is an evolutionarily conserved lysosomal-dependent degradation pathway that is critical in maintaining cellular homeostasis. However, in cancer, autophagy may have conflicting functions in preventing early tumour formation versus the maintenance of advanced-stage tumours. Defective autophagy has a broad and dynamic effect not just on cancer cells, but also on the tumour microenvironment which influences tumour progression and response to treatment. To add to the layer of complexity, somatic mutations in CRC including tumour protein p53 (TP53), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), Kirsten rat sarcoma viral oncogene homolog (KRAS), and phosphatase and tensin homolog (PTEN) can render chemoresistance by promoting a pro-survival advantage through autophagy. Recent studies have also reported autophagy-related cell deaths that are distinct from classical autophagy by employing parts of the autophagic machinery, which impacts strategies for autophagy regulation in cancer therapy. This review discusses the molecular processes of autophagy in the evolution of CRC and its role in the tumour microenvironment, as well as prospective therapeutic methods based on autophagy suppression or promotion. It also highlights clinical trials using autophagy modulators for treating CRC, underscoring the importance of autophagy regulation in CRC therapy.
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Affiliation(s)
- Deepa Rajendran
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
| | - Chern Ein Oon
- Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia.
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Lin L, Lin Y, Han Z, Wang K, Zhou S, Wang Z, Wang S, Chen H. Understanding the molecular regulatory mechanisms of autophagy in lung disease pathogenesis. Front Immunol 2024; 15:1460023. [PMID: 39544928 PMCID: PMC11560454 DOI: 10.3389/fimmu.2024.1460023] [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: 07/05/2024] [Accepted: 10/07/2024] [Indexed: 11/17/2024] Open
Abstract
Lung disease development involves multiple cellular processes, including inflammation, cell death, and proliferation. Research increasingly indicates that autophagy and its regulatory proteins can influence inflammation, programmed cell death, cell proliferation, and innate immune responses. Autophagy plays a vital role in the maintenance of homeostasis and the adaptation of eukaryotic cells to stress by enabling the chelation, transport, and degradation of subcellular components, including proteins and organelles. This process is essential for sustaining cellular balance and ensuring the health of the mitochondrial population. Recent studies have begun to explore the connection between autophagy and the development of different lung diseases. This article reviews the latest findings on the molecular regulatory mechanisms of autophagy in lung diseases, with an emphasis on potential targeted therapies for autophagy.
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Affiliation(s)
- Lin Lin
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yumeng Lin
- Nanjing Tongren Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zhongyu Han
- School of Medicine, Southeast University, Nanjing, China
- Science Education Department, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
| | - Ke Wang
- Department of Science and Education, Deyang Hospital Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Deyang, China
| | - Shuwei Zhou
- Department of Radiology, Zhongda Hospital, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology, School of Medicine, Southeast University, Nanjing, China
| | - Zhanzhan Wang
- Department of Respiratory and Critical Care Medicine, The First People’s Hospital of Lianyungang, Lianyungang, China
| | - Siyu Wang
- Department of Preventive Medicine, Kunshan Hospital of Chinese Medicine, Kunshan, China
| | - Haoran Chen
- Science Education Department, Chengdu Xinhua Hospital Affiliated to North Sichuan Medical College, Chengdu, China
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Cai S, Ye L, Zhong Q, Zhang X. Silencing EPHB2 diminished the malignant biological properties of esophagus cancer cells by blocking autophagy and Wnt/β-catenin pathway. J Biochem Mol Toxicol 2024; 38:e23853. [PMID: 39291656 DOI: 10.1002/jbt.23853] [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: 05/16/2024] [Revised: 07/25/2024] [Accepted: 09/06/2024] [Indexed: 09/19/2024]
Abstract
Eph receptor B2 (EPHB2) is overexpressed in some tumors and relevant to unfavorable outcomes of tumor patients. By searching Gene Expression Profiling Interactive Analysis and KM Plot websites, we discovered that EPHB2 was highly expressed in patients with esophageal cancer, leading to poor prognosis. However, the role and molecular mechanism of EPHB2 in esophagus cancer is unknown. Our study aims to unveil the underlying mechanism by which EPHB2 modulates the biological properties of esophagus cancer cells. After si-EPHB2 transfection, the malignant biological properties of esophagus cancer cells were determined by several biological experiments. IWP-4 was applied to block Wnt/β-catenin signaling pathway. The expressions of autophagy and Wnt/β-catenin signaling pathway relevant molecules were tested by western blot assay. An increased expression of EPHB2 was happened in esophagus cancer samples and loss of EPHB2 diminished esophagus cancer cells proliferation, migration, and invasion. Moreover, our data showed that depletion of EPHB2 blocked the autophagy and in-activated Wnt/β-catenin signaling pathway in esophagus cancer cells. While, IWP-4 treatment inhibited the autophagy and limited esophagus cancer cells proliferation, migration, and invasion. Moreover, EPHB2 knocked down strengthened the effect of IWP-4 treatment in regulating esophagus cancer cells proliferation, migration, and invasion. Finally, we illustrated that EPHB2 regulated the biological properties of esophagus cancer cells by modulating autophagy and Wnt/β-catenin signaling pathway. Our study illustrated that EPHB2 might be a worthwhile target considering for the treatment of esophagus cancer.
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Affiliation(s)
- Shusheng Cai
- Department of Digestive System, The First Affiliated Hospital of Jinzhou Medical University, 2 Section 5, Renmin Street, Guta District, Jinzhou City, Liaoning Province, China
| | - Lianhua Ye
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, 2 Section 5, Renmin Street, Guta District, Jinzhou City, Liaoning Province, China
| | - Qiming Zhong
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, 2 Section 5, Renmin Street, Guta District, Jinzhou City, Liaoning Province, China
| | - Xin Zhang
- Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, 2 Section 5, Renmin Street, Guta District, Jinzhou City, Liaoning Province, China
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Stoyanov M, Martinikova AS, Matejkova K, Horackova K, Zemankova P, Burdova K, Zemanova Z, Kleiblova P, Kleibl Z, Macurek L. PPM1D activity promotes cellular transformation by preventing senescence and cell death. Oncogene 2024; 43:3081-3093. [PMID: 39237765 PMCID: PMC11473410 DOI: 10.1038/s41388-024-03149-3] [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: 05/02/2024] [Revised: 08/23/2024] [Accepted: 08/29/2024] [Indexed: 09/07/2024]
Abstract
Cell cycle checkpoints, oncogene-induced senescence and programmed cell death represent intrinsic barriers to tumorigenesis. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of the tumour suppressor p53 and has been implicated in termination of the DNA damage response. Here, we addressed the consequences of increased PPM1D activity resulting from the gain-of-function truncating mutations in exon 6 of the PPM1D. We show that while control cells permanently exit the cell cycle and reside in senescence in the presence of DNA damage caused by ionising radiation or replication stress induced by the active RAS oncogene, RPE1-hTERT and BJ-hTERT cells carrying the truncated PPM1D continue proliferation in the presence of DNA damage, form micronuclei and accumulate genomic rearrangements revealed by karyotyping. Further, we show that increased PPM1D activity promotes cell growth in the soft agar and formation of tumours in xenograft models. Finally, expression profiling of the transformed clones revealed dysregulation of several oncogenic and tumour suppressor pathways. Our data support the oncogenic potential of PPM1D in the context of exposure to ionising radiation and oncogene-induced replication stress.
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Affiliation(s)
- Miroslav Stoyanov
- Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Andra S Martinikova
- Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Katerina Matejkova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- Department of Genetics and Microbiology, Faculty of Science, Charles University, Prague, Czech Republic
| | - Klara Horackova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Petra Zemankova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Kamila Burdova
- Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Zuzana Zemanova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Petra Kleiblova
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Zdenek Kleibl
- Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Libor Macurek
- Cancer Cell Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic.
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Liu T, Yue X, Chen X, Yan R, Wu C, Li Y, Bu X, Han H, Liu RY. Nilotinib in combination with sunitinib renders MCL-1 for degradation and activates autophagy that overcomes sunitinib resistance in renal cell carcinoma. Cell Oncol (Dordr) 2024; 47:1277-1294. [PMID: 38393513 DOI: 10.1007/s13402-024-00927-9] [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] [Accepted: 02/14/2024] [Indexed: 02/25/2024] Open
Abstract
PURPOSE Sunitinib is a recommended drug for metastatic renal cell carcinoma (RCC). However, the therapeutic potential of sunitinib is impaired by toxicity and resistance. Therefore, we seek to explore a combinatorial strategy to improve sunitinib efficacy of low-toxicity dose for better clinical application. METHODS We screen synergistic reagents of sunitinib from a compound library containing 1374 FDA-approved drugs by in vitro cell viability evaluation. The synergistically antiproliferative and proapoptotic effects were demonstrated on in vitro and in vivo models. The molecular mechanism was investigated by phosphoproteomics, co-immunoprecipitation, immunofluorescence and western-blot assays, etc. RESULTS: From the four-step screening, nilotinib stood out as a potential synergistic killer combined with sunitinib. Subsequent functional evaluation demonstrated that nilotinib and sunitinib synergistically inhibit RCC cell proliferation and promote apoptosis in vitro and in vivo. Mechanistically, nilotinib activates E3-ligase HUWE1 and in combination with sunitinib renders MCL-1 for degradation via proteasome pathway, resulting in the release of Beclin-1 from MCL-1/Beclin-1 complex. Subsequently, Beclin-1 induces complete autophagy flux to promote antitumor effect. CONCLUSION Our findings revealed that a novel mechanism that nilotinib in combination with sunitinib overcomes sunitinib resistance in RCC. Therefore, this novel rational combination regimen provides a promising therapeutic avenue for metastatic RCC and rationale for evaluating this combination clinically.
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Affiliation(s)
- Tingyu Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Xin Yue
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China.
| | - Xue Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Ru Yan
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Chong Wu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yunzhi Li
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Xianzhang Bu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Hui Han
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
| | - Ran-Yi Liu
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
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13
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Köse SG, Güleç Taşkıran AE. Mechanisms of drug resistance in nutrient-depleted colorectal cancer cells: insights into lysosomal and mitochondrial drug sequestration. Biol Open 2024; 13:bio060448. [PMID: 39445740 PMCID: PMC11554266 DOI: 10.1242/bio.060448] [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] [Indexed: 10/25/2024] Open
Abstract
This Review delves into the mechanisms behind drug resistance in colorectal cancer (CRC), particularly examining the role of nutrient depletion and its contribution to multidrug resistance (MDR). The study highlights metabolic adaptations of cancer cells as well as metabolic adaptations of cancer cells under low nutrient availability, including shifts in glycolysis and lipid metabolism. It emphasizes the significance of MDR1 and its encoded efflux transporter, P-glycoprotein (P-gp/B1), in mediating drug resistance and how pathways such as HIF1α, AKT, and mTOR influence the expression of P-gp/B1 under limited nutrient availability. Additionally, the Review explores the dual roles of autophagy in drug sensitivity and resistance under nutrient limited conditions. It further investigates the involvement of lysosomes and mitochondria, focusing on their roles in drug sequestration and the challenges posed by lysosomal entrapment facilitated by non-enzymatic processes and ABC transporters like P-gp/B1. Finally, the Review underscores the importance of understanding the interplay between drug sequestration, lysosomal functions, nutrient depletion, and MDR1 gene modulation. It suggests innovative strategies, including structural modifications and nanotechnology, as promising approaches to overcoming drug resistance in cancer therapy.
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Affiliation(s)
- Serra Gülse Köse
- Molecular Biology and Genetics Department, Baskent University, Ankara 06790, Turkey
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14
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Tao Y, Ding X, Jia C, Wang C, Li C. Using protein turnover assay to explore the drug mechanism of Carfilzomib. Acta Biochim Biophys Sin (Shanghai) 2024; 57:209-222. [PMID: 38978505 PMCID: PMC11877146 DOI: 10.3724/abbs.2024104] [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: 02/17/2024] [Accepted: 05/06/2024] [Indexed: 07/10/2024] Open
Abstract
Carfilzomib (CFZ) is the second-generation proteasome inhibitor that is approved by Food and Drug Administration (FDA) of USA for the treatment of relapsed and refractory multiple myeloma. Although the preclinical and clinical efficacy of CFZ is obvious, the mechanism by which CFZ leads to cell death has not been fully elucidated. Since CFZ primarily functions as a proteasome inhibitor, profiling CFZ-induced changes in protein turnover at the systematic level is sufficient and necessary. In this study, we characterize the effects of CFZ on the stability of 15,000 human proteins using Protein Turnover Assay (ProTA). CFZ affects fundamental cellular glycolysis, nitric oxide production and proteasome subunit homeostasis in multiple myeloma cells. In addition, LY294002 or KU-0063794 has synergistic effects with CFZ in multiple myeloma treatment. A profound understanding of how cells respond to chemotherapeutic agents provides insights into the basic mechanism of drug function and the rationale for CFZ combination therapy.
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Affiliation(s)
- Yonghui Tao
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of EducationKey Laboratory of Molecular Biology in Medical SciencesZhejiang ProvinceChina)the Second Affiliated HospitalZhejiang University School of MedicineHangzhou310009China
- State Key Laboratory of Molecular BiologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China
| | - Xinyu Ding
- Department of Thoracic SurgeryShanghai Pulmonary HospitalTongji University School of MedicineShanghai200433China
| | - Caiwei Jia
- State Key Laboratory of Molecular BiologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China
| | | | - Chuanyin Li
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and InterventionChina National Ministry of EducationKey Laboratory of Molecular Biology in Medical SciencesZhejiang ProvinceChina)the Second Affiliated HospitalZhejiang University School of MedicineHangzhou310009China
- State Key Laboratory of Molecular BiologyShanghai Institute of Biochemistry and Cell BiologyCenter for Excellence in Molecular Cell ScienceUniversity of Chinese Academy of SciencesChinese Academy of SciencesShanghai200031China
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15
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Deng H, Han Y, Liu L, Zhang H, Liu D, Wen J, Huang M, Zhao L. Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions. J Med Chem 2024; 67:5963-5998. [PMID: 38597264 DOI: 10.1021/acs.jmedchem.3c01998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/11/2024]
Abstract
As a tripartite cell death switch, B-cell lymphoma protein 2 (Bcl-2) family members precisely regulate the endogenous apoptosis pathway in response to various cell signal stresses through protein-protein interactions. Myeloid leukemia-1 (Mcl-1), a key anti-apoptotic Bcl-2 family member, is positioned downstream in the endogenous apoptotic pathway and plays a central role in regulating mitochondrial function. Mcl-1 is highly expressed in a variety of hematological malignancies and solid tumors, contributing to tumorigenesis, poor prognosis, and chemoresistance, making it an attractive target for cancer treatment. This Perspective aims to discuss the mechanism by which Mcl-1 regulates apoptosis and non-apoptotic functions in cancer cells and to outline the discovery and optimization process of potent Mcl-1 modulators. In addition, we summarize the structural characteristics of potent inhibitors that bind to Mcl-1 through multiple co-crystal structures and analyze the cardiotoxicity caused by current Mcl-1 inhibitors, providing prospects for rational targeting of Mcl-1.
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Affiliation(s)
- Hongguang Deng
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Yu Han
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Liang Liu
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Hong Zhang
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Dan Liu
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Jiachen Wen
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Min Huang
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
| | - Linxiang Zhao
- Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
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16
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Gulia S, Chandra P, Das A. The Prognosis of Cancer Depends on the Interplay of Autophagy, Apoptosis, and Anoikis within the Tumor Microenvironment. Cell Biochem Biophys 2023; 81:621-658. [PMID: 37787970 DOI: 10.1007/s12013-023-01179-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/15/2023] [Indexed: 10/04/2023]
Abstract
Within the tumor microenvironment, the fight between the immune system and cancer influences tumor transformation. Metastasis formation is an important stage in the progression of cancer. This process is aided by cellular detachment and resistance to anoikis, which are achieved by altering intercellular signaling. Autophagy, specifically pro-survival autophagy, aids cancer cells in developing treatment resistance. Numerous studies have shown that autophagy promotes tumor growth and resistance to anoikis. To regulate protective autophagy, cancer-related genes phosphorylate both pro- and anti-apoptotic proteins. Apoptosis, a type of controlled cell death, eliminates damaged or unwanted cells. Anoikis is a type of programmed cell death in which cells lose contact with the extracellular matrix. The dysregulation of these cellular pathways promotes tumor growth and spread. Apoptosis, anoikis, and autophagy interact meticulously and differently depending on the cellular circumstances. For instance, autophagy can protect cancer cells from apoptosis by removing cellular components that are damaged and might otherwise trigger apoptotic pathways. Similarly, anoikis dysregulation can trigger autophagy by causing cellular harm and metabolic stress. In order to prevent or treat metastatic disease, specifically, targeting these cellular mechanisms may present a promising prospect for cancer therapy. This review discourses the state of our understanding of the molecular and cellular mechanisms underlying tumor transformation and the establishment of metastatic tumors. To enhance the prognosis for cancer, we highlight and discuss potential therapeutic approaches that target these processes and genes involved in them.
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Affiliation(s)
- Shweta Gulia
- Department of Biotechnology, Delhi Technological University, Main Bawana Road, Delhi, 110042, India
| | - Prakash Chandra
- Department of Biotechnology, Delhi Technological University, Main Bawana Road, Delhi, 110042, India
| | - Asmita Das
- Department of Biotechnology, Delhi Technological University, Main Bawana Road, Delhi, 110042, India.
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17
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Gil-Jaramillo N, Aristizábal-Pachón AF, Luque Aleman MA, González Gómez V, Escobar Hurtado HD, Girón Pinto LC, Jaime Camacho JS, Rojas-Cruz AF, González-Giraldo Y, Pinzón A, González J. Competing endogenous RNAs in human astrocytes: crosstalk and interacting networks in response to lipotoxicity. Front Neurosci 2023; 17:1195840. [PMID: 38027526 PMCID: PMC10679742 DOI: 10.3389/fnins.2023.1195840] [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: 03/29/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Neurodegenerative diseases (NDs) are characterized by a progressive deterioration of neuronal function, leading to motor and cognitive damage in patients. Astrocytes are essential for maintaining brain homeostasis, and their functional impairment is increasingly recognized as central to the etiology of various NDs. Such impairment can be induced by toxic insults with palmitic acid (PA), a common fatty acid, that disrupts autophagy, increases reactive oxygen species, and triggers inflammation. Although the effects of PA on astrocytes have been addressed, most aspects of the dynamics of this fatty acid remain unknown. Additionally, there is still no model that satisfactorily explains how astroglia goes from being neuroprotective to neurotoxic. Current incomplete knowledge needs to be improved by the growing field of non-coding RNAs (ncRNAs), which is proven to be related to NDs, where the complexity of the interactions among these molecules and how they control other RNA expressions need to be addressed. In the present study, we present an extensive competing endogenous RNA (ceRNA) network using transcriptomic data from normal human astrocyte (NHA) cells exposed to PA lipotoxic conditions and experimentally validated data on ncRNA interaction. The obtained network contains 7 lncRNA transcripts, 38 miRNAs, and 239 mRNAs that showed enrichment in ND-related processes, such as fatty acid metabolism and biosynthesis, FoxO and TGF-β signaling pathways, prion diseases, apoptosis, and immune-related pathways. In addition, the transcriptomic profile was used to propose 22 potential key controllers lncRNA/miRNA/mRNA axes in ND mechanisms. The relevance of five of these axes was corroborated by the miRNA expression data obtained in other studies. MEG3 (ENST00000398461)/hsa-let-7d-5p/ATF6B axis showed importance in Parkinson's and late Alzheimer's diseases, while AC092687.3/hsa-let-7e-5p/[SREBF2, FNIP1, PMAIP1] and SDCBP2-AS1 (ENST00000446423)/hsa-miR-101-3p/MAPK6 axes are probably related to Alzheimer's disease development and pathology. The presented network and axes will help to understand the PA-induced mechanisms in astrocytes, leading to protection or injury in the CNS under lipotoxic conditions as part of the intricated cellular regulation influencing the pathology of different NDs. Furthermore, the five corroborated axes could be considered study targets for new pharmacologic treatments or as possible diagnostic molecules, contributing to improving the quality of life of millions worldwide.
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Affiliation(s)
- Natalia Gil-Jaramillo
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | | | - María Alejandra Luque Aleman
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Valentina González Gómez
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Hans Deyvy Escobar Hurtado
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Laura Camila Girón Pinto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Juan Sebastian Jaime Camacho
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Alexis Felipe Rojas-Cruz
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Yeimy González-Giraldo
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Andrés Pinzón
- Laboratorio de Bioinformática y Biología de Sistemas, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Janneth González
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
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18
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Huang Y, Zhen Y, Chen Y, Sui S, Zhang L. Unraveling the interplay between RAS/RAF/MEK/ERK signaling pathway and autophagy in cancer: From molecular mechanisms to targeted therapy. Biochem Pharmacol 2023; 217:115842. [PMID: 37802240 DOI: 10.1016/j.bcp.2023.115842] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/28/2023] [Accepted: 10/02/2023] [Indexed: 10/08/2023]
Abstract
RAS/RAF/MEK/ERK signaling pathway is one of the most important pathways of Mitogen-activated protein kinases (MAPK), which widely participate in regulating cell proliferation, differentiation, apoptosis and signaling transduction. Autophagy is an essential mechanism that maintains cellular homeostasis by degrading aged and damaged organelles. Recently, some studies revealed RAS/RAF/MEK/ERK signaling pathway is closely related to autophagy regulation and has a dual effect in tumor cells. However, the specific mechanism by which RAS/RAF/MEK/ERK signaling pathway participates in autophagy regulation is not fully understood. This article provides a comprehensive review of the research progress with regard to the RAS/RAF/MEK/ERK signaling pathway and autophagy, as well as their interplay in cancer therapy. The impact of small molecule inhibitors that target the RAS/RAF/MEK/ERK signaling pathway on autophagy is discussed in this study. The advantages and limitations of the clinical combination of these small molecule inhibitors with autophagy inhibitors are also explored. The findings from this study may provide additional perspectives for future cancer treatment strategies.
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Affiliation(s)
- Yunli Huang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China
| | - Yongqi Zhen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yanmei Chen
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Shaoguang Sui
- Emergency Department, The Second Hospital, Dalian Medical University, Dalian 116000, China.
| | - Lan Zhang
- Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
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19
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Zheng Z, Han L, Li Y, Chen Z, Yang W, Liu C, Tao M, Jiang Y, Ke X, Liu Y, Guo X. Phospholipase A2-activating protein induces mitophagy trough anti-apoptotic MCL1-mediated NLRX1 oligomerization. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2023:119487. [PMID: 37211156 DOI: 10.1016/j.bbamcr.2023.119487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 04/17/2023] [Accepted: 05/11/2023] [Indexed: 05/23/2023]
Abstract
Mitochondrial protein homeostasis is fine-tuned by diverse physiological processes such as mitochondria-associated degradation (MAD), which is regulated by valosin-containing protein (VCP) and its cofactors. As a cofactor of VCP, the mutation of phospholipase A-2-activating protein (PLAA) is the genetic cause of PLAA-associated neurodevelopmental disorder (PLAAND). However, the physiological and pathological roles of PLAA in mitochondria remain unclear. Here, we demonstrate that PLAA partially associates with mitochondria. Deficiency in PLAA increases mitochondrial reactive oxygen species (ROS) production, reduces mitochondrial membrane potential, inhibits mitochondrial respiratory activity and causes excessive mitophagy. Mechanically, PLAA interacts with myeloid cell leukemia-1 (MCL1) and facilitates its retro-translocation and proteasome-dependent degradation. The upregulation of MCL1 promotes the oligomerization of NLR family member X1 (NLRX1) and activation of mitophagy. Whereas downregulating NLRX1 abolishes MCL1 induced mitophagy. In summary, our data identify PLAA as a novel mediator of mitophagy by regulating MCL1-NLRX1 axis. We propose mitophagy as a target for therapeutic intervention in PLAAND.
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Affiliation(s)
- Zhilong Zheng
- Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China
| | - Lu Han
- Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China; Child Mental Health Research Center, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yuanbo Li
- Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhen Chen
- Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wangju Yang
- Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chunyue Liu
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Mengdan Tao
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yueqing Jiang
- Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoyan Ke
- Child Mental Health Research Center, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Yan Liu
- Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Xing Guo
- Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.
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20
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Yang H, Zhang K, Guo Y, Guo X, Hou K, Hou J, Luo Y, Liu J, Jia S. Gain-of-Function p53N236S Mutation Drives the Bypassing of HRas V12-Induced Cellular Senescence via PGC-1α. Int J Mol Sci 2023; 24:ijms24043790. [PMID: 36835200 PMCID: PMC9960896 DOI: 10.3390/ijms24043790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/16/2023] Open
Abstract
One of the key steps in tumorigenic transformation is immortalization in which cells bypass cancer-initiating barriers such as senescence. Senescence can be triggered by either telomere erosion or oncogenic stress (oncogene-induced senescence, OIS) and undergo p53- or Rb-dependent cell cycle arrest. The tumor suppressor p53 is mutated in 50% of human cancers. In this study, we generated p53N236S (p53S) mutant knock-in mice and observed that p53S heterozygous mouse embryonic fibroblasts (p53S/+) escaped HRasV12-induced senescence after subculture in vitro and formed tumors after subcutaneous injection into severe combined immune deficiency (SCID) mice. We found that p53S increased the level and nuclear translocation of PGC-1α in late-stage p53S/++Ras cells (LS cells, which bypassed the OIS). The increase in PGC-1α promoted the biosynthesis and function of mitochondria in LS cells by inhibiting senescence-associated reactive oxygen species (ROS) and ROS-induced autophagy. In addition, p53S regulated the interaction between PGC-1α and PPARγ and promoted lipid synthesis, which may indicate an auxiliary pathway for facilitating cell escape from aging. Our results illuminate the mechanisms underlying p53S mutant-regulated senescence bypass and demonstrate the role played by PGC-1α in this process.
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21
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Ahmadi-Dehlaghi F, Mohammadi P, Valipour E, Pournaghi P, Kiani S, Mansouri K. Autophagy: A challengeable paradox in cancer treatment. Cancer Med 2023. [PMID: 36760166 DOI: 10.1002/cam4.5577] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 11/14/2022] [Accepted: 12/21/2022] [Indexed: 02/11/2023] Open
Abstract
OBJECTIVE Autophagy is an intracellular degradation pathway conserved in all eukaryotes from yeast to humans. This process plays a quality-control role by destroying harmful cellular components under normal conditions, maintaining cell survival, and establishing cellular adaptation under stressful conditions. Hence, there are various studies indicating dysfunctional autophagy as a factor involved in the development and progression of various human diseases, including cancer. In addition, the importance of autophagy in the development of cancer has been highlighted by paradoxical roles, as a cytoprotective and cytotoxic mechanism. Despite extensive research in the field of cancer, there are many questions and challenges about the roles and effects suggested for autophagy in cancer treatment. The aim of this study was to provide an overview of the paradoxical roles of autophagy in different tumors and related cancer treatment options. METHODS In this study, to find articles, a search was made in PubMed and Google scholar databases with the keywords Autophagy, Autophagy in Cancer Management, and Drug Design. RESULTS According to the investigation, some studies suggest that several advanced cancers are dependent on autophagy for cell survival, so when cancer cells are exposed to therapy, autophagy is induced and suppresses the anti-cancer effects of therapeutic agents and also results in cell resistance. However, enhanced autophagy from using anti-cancer drugs causes autophagy-mediated cell death in several cancers. Because autophagy also plays roles in both tumor suppression and promotion further research is needed to determine the precise mechanism of this process in cancer treatment. CONCLUSION We concluded in this article, autophagy manipulation may either promote or hinder the growth and development of cancer according to the origin of the cancer cells, the type of cancer, and the behavior of the cancer cells exposed to treatment. Thus, before starting treatment it is necessary to determine the basal levels of autophagy in various cancers.
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Affiliation(s)
- Farnaz Ahmadi-Dehlaghi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Biology, Payame Noor University, Tehran, Iran
| | - Parisa Mohammadi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Elahe Valipour
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Sarah Kiani
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
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22
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Kim YW, Bak SB, Lee WY, Bae SJ, Lee EH, Yang JH, Kim KY, Song CH, Kim SC, Yun UJ, Park KI. Systemic and molecular analysis dissect the red ginseng induction of apoptosis and autophagy in HCC as mediated with AMPK. J Ginseng Res 2023; 47:479-491. [DOI: 10.1016/j.jgr.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 01/17/2023] [Accepted: 02/12/2023] [Indexed: 02/25/2023] Open
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23
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Ko TK, Tan DJY. Is Disrupted Mitophagy a Central Player to Parkinson's Disease Pathology? Cureus 2023; 15:e35458. [PMID: 36860818 PMCID: PMC9969326 DOI: 10.7759/cureus.35458] [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] [Accepted: 02/25/2023] [Indexed: 02/27/2023] Open
Abstract
Whilst the pathophysiology at a cellular level has been defined, the cause of Parkinson's disease (PD) remains poorly understood. This neurodegenerative disorder is associated with impaired dopamine transmission in the substantia nigra, and protein accumulations known as Lewy bodies are visible in affected neurons. Cell culture models of PD have indicated impaired mitochondrial function, so the focus of this paper is on the quality control processes involved in and around mitochondria. Mitochondrial autophagy (mitophagy) is the process through which defective mitochondria are removed from the cell by internalisation into autophagosomes which fuse with a lysosome. This process involves many proteins, notably including PINK1 and parkin, both of which are known to be coded on genes associated with PD. Normally in healthy individuals, PINK1 associates with the outer mitochondrial membrane, which then recruits parkin, activating it to attach ubiquitin proteins to the mitochondrial membrane. PINK1, parkin, and ubiquitin cooperate to form a positive feedback system which accelerates the deposition of ubiquitin on dysfunctional mitochondria, resulting in mitophagy. However, in hereditary PD, the genes encoding PINK1 and parkin are mutated, resulting in proteins that are less efficient at removing poorly performing mitochondria, leaving cells more vulnerable to oxidative stress and ubiquitinated inclusion bodies, such as Lewy bodies. Current research that looks into the connection between mitophagy and PD is promising, already yielding potentially therapeutic compounds; until now, pharmacological support for the mitophagy process has not been part of the therapeutic arsenal. Continued research in this area is warranted.
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Affiliation(s)
- Tsz Ki Ko
- Otolaryngology, College of Life Sciences, Leicester Medical School, George Davies Centre, Leicester, GBR
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24
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Iachettini S, Ciccarone F, Maresca C, D' Angelo C, Petti E, Di Vito S, Ciriolo MR, Zizza P, Biroccio A. The telomeric protein TERF2/TRF2 impairs HMGB1-driven autophagy. Autophagy 2022:1-12. [PMID: 36310382 DOI: 10.1080/15548627.2022.2138687] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2023] Open
Abstract
TERF2/TRF2 is a pleiotropic telomeric protein that plays a crucial role in tumor formation and progression through several telomere-dependent and -independent mechanisms. Here, we uncovered a novel function for this protein in regulating the macroautophagic/autophagic process upon different stimuli. By using both biochemical and cell biology approaches, we found that TERF2 binds to the non-histone chromatin-associated protein HMGB1, and this interaction is functional to the nuclear/cytoplasmic protein localization. Specifically, silencing of TERF2 alters the redox status of the cells, further exacerbated upon EBSS nutrient starvation, promoting the cytosolic translocation and the autophagic activity of HMGB1. Conversely, overexpression of wild-type TERF2, but not the mutant unable to bind HMGB1, negatively affects the cytosolic translocation of HMGB1, counteracting the stimulatory effect of EBSS starvation. Moreover, genetic depletion of HMGB1 or treatment with inflachromene, a specific inhibitor of its cytosolic translocation, completely abolished the pro-autophagic activity of TERF2 silencing. In conclusion, our data highlighted a novel mechanism through which TERF2 modulates the autophagic process, thus demonstrating the key role of the telomeric protein in regulating a process that is fundamental, under both physiological and pathological conditions, in defining the fate of the cells.Abbreviations: ALs: autolysosomes; ALT: alternative lengthening of telomeres; ATG: autophagy related; ATM: ATM serine/threonine kinase; CQ: Chloroquine; DCFDA: 2',7'-dichlorofluorescein diacetate; DDR: DNA damage response; DHE: dihydroethidium; EBSS: Earle's balanced salt solution; FACS: fluorescence-activated cell sorting; GFP: green fluorescent protein; EGFP: enhanced green fluorescent protein; GSH: reduced glutathione; GSSG: oxidized glutathione; HMGB1: high mobility group box 1; ICM: inflachromene; IF: immunofluorescence; IP: immunoprecipitation; NAC: N-acetyl-L-cysteine; NHEJ: non-homologous end joining; PLA: proximity ligation assay; RFP: red fluorescent protein; ROS: reactive oxygen species; TIF: telomere-induced foci; TERF2/TRF2: telomeric repeat binding factor 2.
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Affiliation(s)
- Sara Iachettini
- Translational Oncology Research Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Fabio Ciccarone
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy.,Biochemistry of aging section, IRCCS San Raffaele Roma, Rome, Italy
| | - Carmen Maresca
- Translational Oncology Research Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Carmen D' Angelo
- Translational Oncology Research Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Eleonora Petti
- Translational Oncology Research Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Serena Di Vito
- Translational Oncology Research Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Maria Rosa Ciriolo
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy.,Biochemistry of aging section, IRCCS San Raffaele Roma, Rome, Italy
| | - Pasquale Zizza
- Translational Oncology Research Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
| | - Annamaria Biroccio
- Translational Oncology Research Unit, IRCCS - Regina Elena National Cancer Institute, Rome, Italy
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25
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Dai R, Zhang L, Jin H, Wang D, Cheng M, Sang T, Peng C, Li Y, Wang Y. Autophagy in renal fibrosis: Protection or promotion? Front Pharmacol 2022; 13:963920. [PMID: 36105212 PMCID: PMC9465674 DOI: 10.3389/fphar.2022.963920] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Autophagy is a process that degrades endogenous cellular protein aggregates and damaged organelles via the lysosomal pathway to maintain cellular homeostasis and energy production. Baseline autophagy in the kidney, which serves as a quality control system, is essential for cellular metabolism and organelle homeostasis. Renal fibrosis is the ultimate pathological manifestation of progressive chronic kidney disease. In several experimental models of renal fibrosis, different time points, stimulus intensities, factors, and molecular mechanisms mediating the upregulation or downregulation of autophagy may have different effects on renal fibrosis. Autophagy occurring in a single lesion may also exert several distinct biological effects on renal fibrosis. Thus, whether autophagy prevents or facilitates renal fibrosis remains a complex and challenging question. This review explores the different effects of the dual regulatory function of autophagy on renal fibrosis in different renal fibrosis models, providing ideas for future work in related basic and clinical research.
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Affiliation(s)
- Rong Dai
- Department of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, China
| | - Lei Zhang
- Department of Nephrology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Hua Jin
- Department of Nephrology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Dong Wang
- Department of Nephrology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Meng Cheng
- Department of Nephrology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Tian Sang
- Graduate School, Anhui University of Chinese Medicine, Hefei, China
| | - Chuyi Peng
- Graduate School, Anhui University of Chinese Medicine, Hefei, China
| | - Yue Li
- Blood Purification Center, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
| | - Yiping Wang
- Department of Nephrology, the First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China
- *Correspondence: Yiping Wang,
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26
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Luo H, Hu L, Brito LF, Dou J, Sammad A, Chang Y, Ma L, Guo G, Liu L, Zhai L, Xu Q, Wang Y. Weighted single-step GWAS and RNA sequencing reveals key candidate genes associated with physiological indicators of heat stress in Holstein cattle. J Anim Sci Biotechnol 2022; 13:108. [PMID: 35986427 PMCID: PMC9392250 DOI: 10.1186/s40104-022-00748-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 06/24/2022] [Indexed: 12/15/2022] Open
Abstract
Background The study of molecular processes regulating heat stress response in dairy cattle is paramount for developing mitigation strategies to improve heat tolerance and animal welfare. Therefore, we aimed to identify quantitative trait loci (QTL) regions associated with three physiological indicators of heat stress response in Holstein cattle, including rectal temperature (RT), respiration rate score (RS), and drooling score (DS). We estimated genetic parameters for all three traits. Subsequently, a weighted single-step genome-wide association study (WssGWAS) was performed based on 3200 genotypes, 151,486 phenotypic records, and 38,101 animals in the pedigree file. The candidate genes located within the identified QTL regions were further investigated through RNA sequencing (RNA-seq) analyses of blood samples for four cows collected in April (non-heat stress group) and four cows collected in July (heat stress group). Results The heritability estimates for RT, RS, and DS were 0.06, 0.04, and 0.03, respectively. Fourteen, 19, and 20 genomic regions explained 2.94%, 3.74%, and 4.01% of the total additive genetic variance of RT, RS, and DS, respectively. Most of these genomic regions are located in the Bos taurus autosome (BTA) BTA3, BTA6, BTA8, BTA12, BTA14, BTA21, and BTA24. No genomic regions overlapped between the three indicators of heat stress, indicating the polygenic nature of heat tolerance and the complementary mechanisms involved in heat stress response. For the RNA-seq analyses, 2627 genes were significantly upregulated and 369 downregulated in the heat stress group in comparison to the control group. When integrating the WssGWAS, RNA-seq results, and existing literature, the key candidate genes associated with physiological indicators of heat stress in Holstein cattle are: PMAIP1, SBK1, TMEM33, GATB, CHORDC1, RTN4IP1, and BTBD7. Conclusions Physiological indicators of heat stress are heritable and can be improved through direct selection. Fifty-three QTL regions associated with heat stress indicators confirm the polygenic nature and complex genetic determinism of heat tolerance in dairy cattle. The identified candidate genes will contribute for optimizing genomic evaluation models by assigning higher weights to genetic markers located in these regions as well as to the design of SNP panels containing polymorphisms located within these candidate genes. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s40104-022-00748-6.
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27
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Liu LC, Shen YC, Wang YL, Wu WR, Chang LC, Chen YH, Lee CC, Wang SC. Growth-promoting function of the cGAS-STING pathway in triple-negative breast cancer cells. Front Oncol 2022; 12:851795. [PMID: 35992877 PMCID: PMC9385397 DOI: 10.3389/fonc.2022.851795] [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: 01/10/2022] [Accepted: 07/13/2022] [Indexed: 11/13/2022] Open
Abstract
The cGAS-STING axis is one of the key mechanisms guarding cells from pathogen invasion in the cytoplasmic compartment. Sensing of foreign DNA in the cytosol by the cGAS-STING axis triggers a stress cascade, culminating at stimulation of the protein kinase TBK1 and subsequently activation of inflammatory response. In cancer cells, aberrant metabolism of the genomic DNA induced by the hostile milieu of tumor microenvironment or stresses brought about by cancer therapeutics are the major causes of the presence of nuclear DNA in the cytosol, which subsequently triggers a stress response. However, how the advanced tumors perceive and tolerate the potentially detrimental effects of cytosolic DNA remains unclear. Here we show that growth limitation by serum starvation activated the cGAS-STING pathway in breast cancer cells, and inhibition of cGAS-STING resulted in cell death through an autophagy-dependent mechanism. These results suggest that, instead of being subject to growth inhibition, tumors exploit the cGAS-STING axis and turn it to a survival advantage in the stressful microenvironment, providing a new therapeutic opportunity against advanced cancer. Concomitant inhibition of the cGAS-STING axis and growth factor signaling mediated by the epidermal growth factor receptor (EGFR) synergistically suppressed the development of tumor organoids derived from primary tumor tissues of triple-negative breast cancer (TNBC). The current study unveils an unexpected function of the cGAS-STING axis in promoting cancer cell survival and the potential of developing the stress-responding pathway as a therapeutic target, meanwhile highlights the substantial concerns of enhancing the pathway's activity as a means of anti-cancer treatment.
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Affiliation(s)
- Liang-Chih Liu
- Department of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Yi-Chun Shen
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Yuan-Liang Wang
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Wan-Rong Wu
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
| | - Ling-Chu Chang
- Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ya-Huey Chen
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chuan-Chun Lee
- Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Shao-Chun Wang
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
- Cancer Biology and Drug Discovery Ph.D. Program, China Medical University, Taichung, Taiwan
- Department of Cancer Biology, University of Cincinnati, Cincinnati, OH, United States
- Department of Biotechnology, Asia University, Taichung, Taiwan
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28
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Ferreira A, Pereira F, Reis C, Oliveira MJ, Sousa MJ, Preto A. Crucial Role of Oncogenic KRAS Mutations in Apoptosis and Autophagy Regulation: Therapeutic Implications. Cells 2022; 11:cells11142183. [PMID: 35883626 PMCID: PMC9319879 DOI: 10.3390/cells11142183] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 07/05/2022] [Accepted: 07/10/2022] [Indexed: 11/16/2022] Open
Abstract
KRAS, one of the RAS protein family members, plays an important role in autophagy and apoptosis, through the regulation of several downstream effectors. In cancer cells, KRAS mutations confer the constitutive activation of this oncogene, stimulating cell proliferation, inducing autophagy, suppressing apoptosis, altering cell metabolism, changing cell motility and invasion and modulating the tumor microenvironment. In order to inhibit apoptosis, these oncogenic mutations were reported to upregulate anti-apoptotic proteins, including Bcl-xL and survivin, and to downregulate proteins related to apoptosis induction, including thymine-DNA glycosylase (TDG) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). In addition, KRAS mutations are known to induce autophagy in order to promote cell survival and tumor progression through MAPK and PI3K regulation. Thus, these mutations confer resistance to anti-cancer drug treatment and, consequently, result in poor prognosis. Several therapies have been developed in order to overcome KRAS-induced cell death resistance and the downstream signaling pathways blockade, especially by combining MAPK and PI3K inhibitors, which demonstrated promising results. Understanding the involvement of KRAS mutations in apoptosis and autophagy regulation, might bring new avenues to the discovery of therapeutic approaches for CRCs harboring KRAS mutations.
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Affiliation(s)
- Anabela Ferreira
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; (A.F.); (F.P.); (M.J.S.)
- Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
| | - Flávia Pereira
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; (A.F.); (F.P.); (M.J.S.)
- Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; (C.R.); (M.J.O.)
- Institute of Biomedical Engineering (INEB), University of Porto, 4200-135 Porto, Portugal
| | - Celso Reis
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; (C.R.); (M.J.O.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal
| | - Maria José Oliveira
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal; (C.R.); (M.J.O.)
- Institute of Biomedical Engineering (INEB), University of Porto, 4200-135 Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal
| | - Maria João Sousa
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; (A.F.); (F.P.); (M.J.S.)
- Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
| | - Ana Preto
- Centre of Molecular and Environmental Biology (CBMA), Department of Biology, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal; (A.F.); (F.P.); (M.J.S.)
- Institute of Science and Innovation for Bio-Sustainability (IB-S), Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal
- Correspondence: ; Tel.: +351-253-601524
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29
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Guo X, Wu C, Pan Y, Zhu X, Peng K, Ma X, Xue L. Mechanistic insights and implications of FOXO-SNAI interplay. Bioessays 2022; 44:e2200070. [PMID: 35832016 DOI: 10.1002/bies.202200070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/29/2021] [Accepted: 07/05/2022] [Indexed: 11/06/2022]
Abstract
Autophagy promotes both health and disease, depending on tissue types and genetic contexts, yet the regulatory mechanism remain incompletely understood. Our recent publication has uncovered a coherent FOXO-SNAI feed-forward loop in autophagy, which is evolutionarily conserved from Drosophila to human. In addition, it's revealed that DNA binding plays a critical role in intracellular localization of nucleocytoplasmic shuttling proteins. Based on these findings, herein we further integrate mechanistic insights of FOXO-SNAI regulatory interplay in autophagy and unravel the potential link of FOXO-induced autophagy with SNAI in diseases. Besides, the generality of DNA-retention mechanism on transcription factor nuclear localization is illustrated with wide-ranging discussion, and more functions potentially regulated by FOXO-SNAI feedforward loop are provided. Elucidation of these unsolved paradigms will expand the understanding of FOXO-SNAI interplay and facilitate the development of new therapeutics targeting FOXO-SNAI axis in diseases.
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Affiliation(s)
- Xiaowei Guo
- School of Medicine, Hunan Normal University, Changsha, Hunan, China.,Institute of Intervention Vessel, Shanghai 10th People's Hospital, School of Life Science and Technology, Tongji University, Shanghai, China
| | - Chenxi Wu
- College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, Hebei, China
| | - Yu Pan
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, School of Life Science and Technology, Tongji University, Shanghai, China
| | - Xiaojie Zhu
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, School of Life Science and Technology, Tongji University, Shanghai, China
| | - Kai Peng
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, School of Life Science and Technology, Tongji University, Shanghai, China
| | - Xianjue Ma
- School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
| | - Lei Xue
- Institute of Intervention Vessel, Shanghai 10th People's Hospital, School of Life Science and Technology, Tongji University, Shanghai, China.,Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong, China
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30
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Zhou J, Yang J, Dong Y, Shi Y, Zhu E, Yuan H, Li X, Wang B. Oncostatin M receptor regulates osteoblast differentiation via extracellular signal-regulated kinase/autophagy signaling. Stem Cell Res Ther 2022; 13:278. [PMID: 35765036 PMCID: PMC9241272 DOI: 10.1186/s13287-022-02958-1] [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: 04/18/2022] [Accepted: 06/12/2022] [Indexed: 11/10/2022] Open
Abstract
Background Oncostatin M receptor (OSMR), as one of the receptors for oncostatin M (OSM), has previously been shown to mediate the stimulatory role of OSM in osteoclastogenesis and bone resorption. However, it remains to be clarified whether and how OSMR affects the differentiation of osteoblasts. Methods The expression level of OSMR during osteoblast and adipocyte differentiation was examined. The role of OSMR in the differentiation was investigated using in vitro gain-of-function and loss-of-function experiments. The mechanisms by which OSMR regulates bone cell differentiation were explored. Finally, in vivo function of OSMR in cell fate determination and bone homeostasis was studied after transplantation of OSMR-silenced bone marrow stromal cells (BMSCs) to the marrow of ovariectomized mice. Results OSMR was regulated during osteogenic and adipogenic differentiation of marrow stromal progenitor cells and increased in the metaphysis of ovariectomized mice. OSMR suppressed osteogenic differentiation and stimulated adipogenic differentiation of progenitor cells. Mechanistic investigations showed that OSMR inhibited extracellular signal-regulated kinase (ERK) and autophagy signaling. The downregulation of autophagy, which was mediated by ERK inhibition, suppressed osteogenic differentiation of progenitor cells. Additionally, inactivation of ERK/autophagy signaling attenuated the stimulation of osteogenic differentiation induced by Osmr siRNA. Furthermore, transplantation of BMSCs in which OSMR was silenced to the marrow of mice promoted osteoblast differentiation, attenuated fat accumulation and osteoclast differentiation, and thereby relieved the osteopenic phenotype in the ovariectomized mice. Conclusions Our study has for the first time established the direct role of OSMR in regulating osteogenic differentiation of marrow stromal progenitor cells through ERK-mediated autophagy signaling. OSMR thus contributes to bone homeostasis through dual regulation of osteoblasts and osteoclasts. It also suggests that OSMR may be a potential target for the treatment of metabolic disorders such as osteoporosis. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02958-1.
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Affiliation(s)
- Jie Zhou
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China
| | - Junying Yang
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China.,College of Basic Medical Sciences, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Tianjin, 300070, China
| | - Yuan Dong
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China.,College of Basic Medical Sciences, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Tianjin, 300070, China
| | - Yaru Shi
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China
| | - Endong Zhu
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China
| | - Hairui Yuan
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China
| | - Xiaoxia Li
- College of Basic Medical Sciences, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Tianjin, 300070, China
| | - Baoli Wang
- NHC Key Lab of Hormones and Development, Tianjin Key Lab of Metabolic Diseases, Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, 6 Huan-Rui-Bei Road, Tianjin, 300134, China.
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31
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Hamedi KR, Harmon KA, Goodwin RL, Arce S. Autophagy and the Bone Marrow Microenvironment: A Review of Protective Factors in the Development and Maintenance of Multiple Myeloma. Front Immunol 2022; 13:889954. [PMID: 35663979 PMCID: PMC9161817 DOI: 10.3389/fimmu.2022.889954] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 04/19/2022] [Indexed: 11/29/2022] Open
Abstract
The role of the unfolded protein response (UPR) in plasma cells (PC) and their malignant multiple myeloma (MM) counterparts is a well described area of research. The importance of autophagy in these cells, as well as the interplay between autophagy and the UPR system, has also been well studied. In this review, we will discuss the relationship between these two cellular responses and how they can be utilized in MM to account for the high levels of monoclonal immunoglobulin (Ig) protein synthesis that is characteristic of this disease. Interactions between MM cells and the bone marrow (BM) microenvironment and how MM cells utilize the UPR/autophagy pathway for their survival. These interacting pathways form the foundation for the mechanism of action for bortezomib, a proteasome inhibitor used to modify the progression of MM, and the eventual drug resistance that MM cells develop. One important resistance pathway implicated in MM progression is caspase 10 which attenuates autophagy to maintain its prosurvival function and avoid cell death. We lay a groundwork for future research including 3D in vitro models for better disease monitoring and personalized treatment. We also highlight pathways involved in MM cell survival and drug resistance that could be used as new targets for effective treatment.
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Affiliation(s)
- Kamron R Hamedi
- University of South Carolina School of Medicine Greenville, University of South Carolina, Greenville, SC, United States
| | - Katrina A Harmon
- Research and Development Department, Organogenesis, Birmingham, AL, United States
| | - Richard L Goodwin
- Biomedical Sciences, University of South Carolina School of Medicine Greenville, University of South Carolina, Greenville, SC, United States
| | - Sergio Arce
- Biomedical Sciences, University of South Carolina School of Medicine Greenville, University of South Carolina, Greenville, SC, United States.,Prisma Health Cancer Institute, Prisma Health System, Greenville, SC, United States
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32
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Arif A, Khawar MB, Mehmood R, Abbasi MH, Sheikh N. Dichotomous role of autophagy in cancer. ASIAN BIOMED 2022; 16:111-120. [PMID: 37551378 PMCID: PMC10321184 DOI: 10.2478/abm-2022-0014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Autophagy is an evolutionary conserved catabolic process that plays physiological and pathological roles in a cell. Its effect on cellular metabolism, the proteome, and the number and quality of organelles, diversely holds the potential to alter cellular functions. It acts paradoxically in cancer as a tumor inhibitor as well as a tumor promoter. In the early stage of tumorigenesis, it prevents tumor initiation by the so-called "quality control mechanism" and suppresses cancer progression. For late-staged tumors that are exposed to stress, it acts as a vibrant process of degradation and recycling that promotes cancer by facilitating metastasis. Despite this dichotomy, the crucial role of autophagy is evident in cancer, and associated with mammalian targets of rapamycin (mTOR), p53, and Ras-derived major cancer networks. Irrespective of the controversy regarding autophagic manipulation, promotion and suppression of autophagy act as potential therapeutic targets in cancer treatment and may provide various anticancer therapies.
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Affiliation(s)
- Amin Arif
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
| | - Muhammad Babar Khawar
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
- Department of Zoology, University of Narowal, Narowal51750, Pakistan
| | - Rabia Mehmood
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
| | - Muddasir Hassan Abbasi
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
- Department of Zoology, University of Okara, Okara56130, Pakistan
| | - Nadeem Sheikh
- Institute of Zoology, University of the Punjab, Lahore54000, Pakistan
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JNK initiates Beclin-1 dependent autophagic cell death against Akt activation. Exp Cell Res 2022; 414:113105. [DOI: 10.1016/j.yexcr.2022.113105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/07/2022] [Accepted: 03/10/2022] [Indexed: 11/24/2022]
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Prerna K, Dubey VK. Beclin1-mediated interplay between autophagy and apoptosis: New understanding. Int J Biol Macromol 2022; 204:258-273. [PMID: 35143849 DOI: 10.1016/j.ijbiomac.2022.02.005] [Citation(s) in RCA: 99] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 01/04/2023]
Abstract
The definition for autophagy holds a 'single' meaning as a conserved cellular process that constitutes a recycling pathway for damaged organelles and long-lived proteins to maintain nutrient homeostasis and mediate quality control within the cell. But this process of autophagy may behave ambiguously depending on the physiological stress as the stress progresses in the cellular microenvironment; the 'single' meaning of the autophagy changes from the 'cytoplasmic turnover process' to 'tumor suppressive' and a farther extent, 'tumor promoter' process. In a tumorigenic state, the chemotherapy-mediated resistance and intolerance due to upregulated autophagy in cancer cells have become a significant concern. This concern has provided insight to the scientific community to enter into the arena of cross-talk between autophagy and apoptosis. Recent findings and ongoing research have provided insights on some of the key regulators of this cross-talk; one of them is Beclin1 and their involvement in the physiological and the pathophysiological processes; however, reconciliation of these two forms of death remains an arena to be explored extensively. This review sheds light on the interplay between autophagy and apoptosis, emphasizing one of the key players, Beclin1, and its importance in health and diseases.
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Affiliation(s)
- Kumari Prerna
- School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi, UP-221005, India
| | - Vikash Kumar Dubey
- School of Biochemical Engineering, Indian Institute of Technology (BHU) Varanasi, UP-221005, India.
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35
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Zhao G, Zhang T, Liu W, Edderkaoui M, Hu R, Li J, Pandol SJ, Fu X, Han YP. Sequestration of Intestinal Acidic Toxins by Cationic Resin Attenuates Pancreatic Cancer Progression through Promoting Autophagic Flux for YAP Degradation. Cancers (Basel) 2022; 14:1407. [PMID: 35326559 PMCID: PMC8946475 DOI: 10.3390/cancers14061407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/25/2022] [Accepted: 02/28/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer is driven by risk factors such as diabetes and chronic pancreatic injury, which are further associated with gut dysbiosis. Intestinal toxins such as bile acids and bacterial endotoxin (LPS), in excess and persistence, can provoke chronic inflammation and tumorigenesis. Of interest is that many intestinal toxins are negatively charged acidic components in essence, which prompted us to test whether oral administration of cationic resin can deplete intestinal toxins and ameliorate pancreatic cancer. Here, we found that increased plasma levels of endotoxin and bile acids in Pdx1-Cre: LSL-KrasG12D/+ mice were associated with the transformation of the pancreatic ductal carcinoma (PDAC) state. Common bile-duct-ligation or LPS injection impeded autolysosomal flux, leading to Yap accumulation and malignant transformation. Conversely, oral administration of cholestyramine to sequestrate intestinal endotoxin and bile acids resumed autolysosomal flux for Yap degradation and attenuated metastatic incidence. Conversely, chloroquine treatment impaired autolysosomal flux and exacerbated malignance, showing jeopardization of p62/ Sqxtm1 turnover, leading to Yap accumulation, which is also consistent with overexpression of cystatin A (CSTA) in situ with pancreatic cancer cells and metastatic tumor. At cellular levels, chenodeoxycholic acid or LPS treatment activated the ligand-receptor-mediated AKT-mTOR pathway, resulting in autophagy-lysosomal stress for YAP accumulation and cellular dissemination. Thus, this work indicates a potential new strategy for intervention of pancreatic metastasis through sequestration of intestinal acidic toxins by oral administration of cationic resins.
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Affiliation(s)
- Guangfu Zhao
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China; (G.Z.); (T.Z.); (W.L.)
| | - Tianci Zhang
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China; (G.Z.); (T.Z.); (W.L.)
| | - Wei Liu
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China; (G.Z.); (T.Z.); (W.L.)
| | - Mouad Edderkaoui
- Cedars-Sinai Medical Center, Los Angeles, CA 90001, USA; (M.E.); (S.J.P.)
| | - Richard Hu
- Olive View-UCLA Medical Center, Los Angeles, CA 90001, USA;
| | - Jun Li
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu 610083, China;
| | - Stephen J. Pandol
- Cedars-Sinai Medical Center, Los Angeles, CA 90001, USA; (M.E.); (S.J.P.)
| | - Xiangsheng Fu
- Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu 610083, China;
| | - Yuan-Ping Han
- The Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu 610017, China; (G.Z.); (T.Z.); (W.L.)
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Yang YF, Wang CM, Hsiao IH, Liu YL, Lin WH, Lin CL, Hung HC, Liu GY. Peptidylarginine deiminase 2 promotes T helper 17-like T cell activation and activated T cell-autonomous death (ACAD) through an endoplasmic reticulum stress and autophagy coupling mechanism. Cell Mol Biol Lett 2022; 27:19. [PMID: 35236296 PMCID: PMC8903576 DOI: 10.1186/s11658-022-00312-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/14/2022] [Indexed: 12/11/2022] Open
Abstract
Peptididylarginine deiminase type 2 (PADI2) catalyzes the conversion of arginine residues to citrulline residues on proteins. We demonstrate that PADI2 induces T cell activation and investigate how PADI2 promotes activated T cell autonomous death (ACAD). In activated Jurkat T cells, overexpression of PADI2 significantly increases citrullinated proteins and induces endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling, ultimately resulting in the expression of autophagy-related proteins and autophagy. PADI2 promoted autophagy and resulted in the early degradation of p62 and the light chain 3B (LC3B)-II accumulation. In Jurkat T cells, silencing the autophagy-related gene (Atg) 12 protein inhibits PADI2-mediated autophagy and promotes ER stress and apoptosis, whereas overexpression of Atg12 decreased ER stress and prolonged autophagy to promote cell survival. Additionally, PADI2 regulates T cell activation and the production of Th17 cytokines in Jurkat T cells (interleukins 6, IL-17A, IL-17F, IL-21, and IL-22). In Jurkat T cells, silencing IL-6 promotes autophagy mediated by PADI2 and inhibits PADI2-induced apoptosis, whereas silencing Beclin-1 increases the activation and survival of Th17-like T cells while decreasing autophagy and apoptosis. PADI2 silencing alleviates ER stress caused by PADI2 and decreases cytokine expression associated with Th17-like T cell activation and ACAD. We propose that PADI2 was involved in Th17 lymphocyte ACAD via a mechanism involving ER stress and autophagy that was tightly regulated by PADI2-mediated citrullination. These findings suggest that inhibiting Th17 T cell activation and the development of severe autoimmune diseases may be possible through the use of novel antagonists that specifically target PADI2.
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Affiliation(s)
- Yi-Fang Yang
- Department of Life Sciences, National Chung Hsing University (NCHU), Taichung, 40227, Taiwan.,Ph.D. Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, 40227, Taiwan
| | - Chuang-Ming Wang
- Department of Pediatrics, Ditmanson Medical Foundation Chia-Yi Christian Hospital (CYCH), Chia-Yi, 60002, Taiwan
| | - I-Hsin Hsiao
- Department of Life Sciences, National Chung Hsing University (NCHU), Taichung, 40227, Taiwan
| | - Yi-Liang Liu
- Department of Life Sciences, National Chung Hsing University (NCHU), Taichung, 40227, Taiwan.,Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan
| | - Wen-Hao Lin
- Department of Life Sciences, National Chung Hsing University (NCHU), Taichung, 40227, Taiwan.,Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan
| | - Chih-Li Lin
- Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan
| | - Hui-Chih Hung
- Department of Life Sciences, National Chung Hsing University (NCHU), Taichung, 40227, Taiwan. .,Institute of Genomics and Bioinformatics, National Chung Hsing University (NCHU), Taichung, 40227, Taiwan. .,iEGG and Animal Biotechnology Center, NCHU, Taichung, 40227, Taiwan.
| | - Guang-Yaw Liu
- Institute of Medicine, School of Medicine, Chung Shan Medical University, Taichung, 40201, Taiwan. .,Department of Allergy, Immunology & Rheumatology, Chung Shan Medical University Hospital, Taichung, 40201, Taiwan.
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Zhang C, Wang Y. KCNQ1OT1 polymorphism rs35622507 and methylation status of KCNQ1OT1 promoter influence the drug resistance to L-OHP. Aging (Albany NY) 2022; 14:1836-1847. [PMID: 35193115 PMCID: PMC8908920 DOI: 10.18632/aging.203906] [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: 07/13/2021] [Accepted: 12/25/2021] [Indexed: 12/24/2022]
Abstract
Background: LncRNA potassium voltage-gated channel subfamily Q member 1 opposite strand/antisense transcript 1 (KCNQ1OT1) has been reported to promote resistance to chemotherapy in colon cancer by inhibiting the expression of miR-34a. And the methylation of KCNQ1OT1 was also reported in the pathogenesis of various diseases. In this study, we aimed to study the combined effect of allele variation of KCNQ1OT1 polymorphism rs35622507 and methylation status of KCNQ1OT1 promoter in the treatment of colon cancer. Methods: The expression levels of KCNQ1OT1, miR-34a, and ATG4B mRNA were assessed by qRT-PCR. ATG4B protein expression was analyzed by Western blot analysis. TUNEL and MTT assay were performed to examine the cell apoptosis and viability. Luciferase assays revealed the relationship between KCNQ1OT1, miR-34a and ATG4B. Results: Carrier of allele 10 and methylated promoter in KCNQ1OT1 was associated with decreased KCNQ1OT1/ATG4B expression, increased miR-34a expression and enhanced apoptosis in colon cancer tissue samples. And subsequent luciferase assay showed that miR-34a could bind to KCNQ1OT1 and ATG4B at specific binding sites. The knockdown of KCNQ1OT1 significantly suppressed the KCNQ1OT1/ATG4B expression, improved the miR-34a expression and reduced the viability of HCT116 and SW480 cells. The over-expression of ATG4B notably restored the cell viability loss and apoptosis increase induced by the knockdown of KCNQ1OT1. Moreover, oxaliplatin (L-OHP) treatment elevated the apoptosis of HCT116 and SW480 cells. Conclusions: The drug resistance in the treatment of colon cancer is most reduced in patients carrying allele 10 and methylated in KCNQ1OT1 promoter. This function is accomplished by the signaling pathway of KCNQ1OT1/miR-34a/ATG4B.
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Affiliation(s)
- Caihong Zhang
- Proctology Department, Xing Yuan Hospital of Yulin, Yulin 719000, Shaanxi, China
| | - Yonglin Wang
- Pharmacy Department, Yangling Demonstration Zone Hospital, Xianyang 712100, Shaanxi, China
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38
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Ji X, Ma H, Du Y. Role and mechanism of action of LAPTM4B in EGFR‑mediated autophagy (Review). Oncol Lett 2022; 23:109. [PMID: 35242237 DOI: 10.3892/ol.2022.13229] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 01/17/2022] [Indexed: 12/09/2022] Open
Affiliation(s)
- Xiaokun Ji
- Department of Cytology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Hua Ma
- Department of Cytology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Yun Du
- Department of Cytology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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39
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Marzoog BA. Autophagy in Cancer Cell Transformation: A Potential Novel Therapeutic Strategy. Curr Cancer Drug Targets 2022; 22:749-756. [PMID: 36062863 DOI: 10.2174/1568009622666220428102741] [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: 03/15/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 01/18/2023]
Abstract
Basal autophagy plays a crucial role in maintaining intracellular homeostasis and prevents the cell from escaping the cell cycle regulation mechanisms and being cancerous. Mitophagy and nucleophagy are essential for cell health. Autophagy plays a pivotal role in cancer cell transformation, where upregulated precancerous autophagy induces apoptosis. Impaired autophagy has been shown to upregulate cancer cell transformation. However, tumor cells upregulate autophagy to escape elimination and survive the unfavorable conditions and resistance to chemotherapy. Cancer cells promote autophagy through modulation of autophagy regulation mechanisms and increase expression of the autophagyrelated genes. Whereas, autophagy regulation mechanisms involved microRNAs, transcription factors, and the internalized signaling pathways such as AMPK, mTOR, III PI3K, and ULK-1. Disrupted regulatory mechanisms are various as the cancer cell polymorphism. Targeting a higher level of autophagy regulation is more effective, such as gene expression, transcription factors, or epigenetic modification that are responsible for the up-regulation of autophagy in cancer cells. Currently, the CRISPR-CAS9 technique is available and can be applied to demonstrate the potential effects of autophagy in cancerous cells.
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Affiliation(s)
- Basheer Abdullah Marzoog
- National Research Mordovia State University, Bolshevitskaya Street, 68, Saransk, Rep. Mordovia 430005, Russian Federation
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40
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Ghafarkhani M, Avci CB, Rahbarghazi R, Karimi A, Sadeghizadeh M, Zarebkohan A, Bani F. Mild hyperthermia induced by gold nanorods acts as a dual-edge blade in the fate of SH-SY5Y cells via autophagy. Sci Rep 2021; 11:23984. [PMID: 34907215 PMCID: PMC8671444 DOI: 10.1038/s41598-021-02697-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023] Open
Abstract
Unraveling unwanted side effects of nanotechnology-based therapies like photothermal therapy (PTT) is vital in translational nanomedicine. Herein, we monitored the relationship between autophagic response at the transcriptional level by using a PCR array and tumor formation ability by colony formation assay in the human neuroblastoma cell line, SH-SY5Y, 48 h after being exposed to two different mild hyperthermia (43 and 48 °C) induced by PTT. In this regard, the promotion of apoptosis and autophagy were evaluated using immunofluorescence imaging and flow cytometry analyses. Protein levels of Ki-67, P62, and LC3 were measured using ELISA. Our results showed that of 86 genes associated with autophagy, the expression of 54 genes was changed in response to PTT. Also, we showed that chaperone-mediated autophagy (CMA) and macroautophagy are stimulated in PTT. Importantly, the results of this study also showed significant changes in genes related to the crosstalk between autophagy, dormancy, and metastatic activity of treated cells. Our findings illustrated that PTT enhances the aggressiveness of cancer cells at 43 °C, in contrast to 48 °C by the regulation of autophagy-dependent manner.
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Affiliation(s)
- Maryam Ghafarkhani
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran
| | - Cigir Biray Avci
- Department of Medical Biology, Medical Faculty, Ege University, Bornova, 35100, Izmir, Turkey
| | - Reza Rahbarghazi
- Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Abbas Karimi
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Majid Sadeghizadeh
- Department of Nanobiotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Zarebkohan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Farhad Bani
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, 516661-4733, Tabriz, Iran.
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Abd El-Aziz YS, Leck LYW, Jansson PJ, Sahni S. Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma. Cancers (Basel) 2021; 13:6152. [PMID: 34944772 PMCID: PMC8699656 DOI: 10.3390/cancers13246152] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a cellular catabolic process, which is characterized by degradation of damaged proteins and organelles needed to supply the cell with essential nutrients. At basal levels, autophagy is important to maintain cellular homeostasis and development. It is also a stress responsive process that allows the cells to survive when subjected to stressful conditions such as nutrient deprivation. Autophagy has been implicated in many pathologies including cancer. It is well established that autophagy plays a dual role in different cancer types. There is emerging role of autophagy in oral squamous cell carcinoma (OSCC) development and progression. This review will focus on the role played by autophagy in relation to different aspects of cancer progression and discuss recent studies exploring the role of autophagy in OSCC. It will further discuss potential therapeutic approaches to target autophagy in OSCC.
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Affiliation(s)
- Yomna S. Abd El-Aziz
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Oral Pathology Department, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Lionel Y. W. Leck
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Patric J. Jansson
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Sydney, NSW 2006, Australia
| | - Sumit Sahni
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; (Y.S.A.E.-A.); (L.Y.W.L.); (P.J.J.)
- Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, St Leonards, NSW 2064, Australia
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42
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Paggi CA, Dudakovic A, Fu Y, Garces CG, Hevesi M, Galeano Garces D, Dietz AB, van Wijnen AJ, Karperien M. Autophagy Is Involved in Mesenchymal Stem Cell Death in Coculture with Chondrocytes. Cartilage 2021; 13:969S-979S. [PMID: 32693629 PMCID: PMC8721613 DOI: 10.1177/1947603520941227] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
OBJECTIVE Cartilage formation is stimulated in mixtures of chondrocytes and human adipose-derived mesenchymal stromal cells (MSCs) both in vitro and in vivo. During coculture, human MSCs perish. The goal of this study is to elucidate the mechanism by which adipose tissue-derived MSC cell death occurs in the presence of chondrocytes. METHODS Human primary chondrocytes were cocultured with human MSCs derived from 3 donors. The cells were cultured in monoculture or coculture (20% chondrocytes and 80% MSCs) in pellets (200,000 cells/pellet) for 7 days in chondrocyte proliferation media in hypoxia (2% O2). RNA sequencing was performed to assess for differences in gene expression between monocultures or coculture. Immune fluorescence assays were performed to determine the presence of caspase-3, LC3B, and P62. RESULTS RNA sequencing revealed significant upregulation of >90 genes in the 3 cocultures when compared with monocultures. STRING analysis showed interconnections between >50 of these genes. Remarkably, 75% of these genes play a role in cell death pathways such as apoptosis and autophagy. Immunofluorescence shows a clear upregulation of the autophagic machinery with no substantial activation of the apoptotic pathway. CONCLUSION In cocultures of human MSCs with primary chondrocytes, autophagy is involved in the disappearance of MSCs. We propose that this sacrificial cell death may contribute to the trophic effects of MSCs on cartilage formation.
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Affiliation(s)
- Carlo Alberto Paggi
- Department of Developmental
BioEngineering, University of Twente, Enschede, Netherlands,Department of Orthopedic Surgery, Mayo
Clinic, Rochester, MN, USA,Department of Biochemistry and Molecular
Biology, Mayo Clinic, Rochester, MN, USA
| | - Amel Dudakovic
- Department of Orthopedic Surgery, Mayo
Clinic, Rochester, MN, USA,Department of Biochemistry and Molecular
Biology, Mayo Clinic, Rochester, MN, USA
| | - Yao Fu
- Department of Developmental
BioEngineering, University of Twente, Enschede, Netherlands
| | | | - Mario Hevesi
- Department of Orthopedic Surgery, Mayo
Clinic, Rochester, MN, USA
| | | | - Allan B. Dietz
- Department of Laboratory Medicine and
Pathology, Mayo Clinic, Rochester, MN, USA
| | - Andre J. van Wijnen
- Department of Orthopedic Surgery, Mayo
Clinic, Rochester, MN, USA,Department of Biochemistry and Molecular
Biology, Mayo Clinic, Rochester, MN, USA,Andre J. van Wijnen, Department of
Orthopedic Surgery, Mayo Clinic, 200 First Street SW, MedSci 3-69, Rochester, MN
5590, USA.
| | - Marcel Karperien
- Department of Developmental
BioEngineering, University of Twente, Enschede, Netherlands,Marcel Karperien, Department of
Developmental BioEngineering, University of Twente, 7522 NB, Enschede,
Netherlands.
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43
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Schmukler E, Pinkas-Kramarski R. The interplay between Ras, Autophagy and cancer. ADVANCES IN CANCER BIOLOGY - METASTASIS 2021; 3:100014. [DOI: 10.1016/j.adcanc.2021.100014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Han S, Li X, Wang K, Zhu D, Meng B, Liu J, Liang X, Jin Y, Liu X, Wen Q, Zhou L. PURPL represses autophagic cell death to promote cutaneous melanoma by modulating ULK1 phosphorylation. Cell Death Dis 2021; 12:1070. [PMID: 34759263 PMCID: PMC8581000 DOI: 10.1038/s41419-021-04362-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/18/2021] [Accepted: 10/27/2021] [Indexed: 01/26/2023]
Abstract
Uncontrolled overactivation of autophagy may lead to autophagic cell death, suppression of which is a pro-survival strategy for tumors. However, mechanisms involving key regulators in modulating autophagic cell death remain poorly defined. Here, we report a novel long noncoding RNA, p53 upregulated regulator of p53 levels (PURPL), functions as an oncogene to promote cell proliferation, colony formation, migration, invasiveness, and inhibits cell death in melanoma cells. Mechanistic studies showed that PURPL promoted mTOR-mediated ULK1 phosphorylation at Ser757 by physical interacting with mTOR and ULK1 to constrain autophagic response to avoid cell death. Loss of PURPL led to AMPK-mediated phosphorylation of ULK1 at Ser555 and Ser317 to over-activate autophagy and induce autophagic cell death. Our results identify PURPL as a key regulator to modulate the activity of autophagy initiation factor ULK1 to repress autophagic cell death in melanoma and may represent a potential intervention target for melanoma therapy.
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Affiliation(s)
- Shuo Han
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Xue Li
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
- School of Clinical Medicine and Technology, Sichuan Vocational College of Health and Rehabilitation, Zigong, China
| | - Ke Wang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Dingheng Zhu
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Bingyao Meng
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Jieyu Liu
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Xiaoting Liang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Yi Jin
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Xingyuan Liu
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Qian Wen
- Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
| | - Liang Zhou
- Department of Toxicology, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China.
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He HQ, Qu YQ, Kwan Law BY, Qiu CL, Han Y, Ricardo de Seabra Rodrigues Dias I, Liu Y, Zhang J, Wu AG, Wu CW, Fai Mok SW, Cheng X, He YZ, Wai Wong VK. AGEs-Induced Calcification and Apoptosis in Human Vascular Smooth Muscle Cells Is Reversed by Inhibition of Autophagy. Front Pharmacol 2021; 12:692431. [PMID: 34744705 PMCID: PMC8564286 DOI: 10.3389/fphar.2021.692431] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 09/29/2021] [Indexed: 01/03/2023] Open
Abstract
Vascular calcification (VC) in macrovascular and peripheral blood vessels is one of the main factors leading to diabetes mellitus (DM) and death. Apart from the induction of vascular calcification, advanced glycation end products (AGEs) have also been reported to modulate autophagy and apoptosis in DM. Autophagy plays a role in maintaining the stabilization of the external and internal microenvironment. This process is vital for regulating arteriosclerosis. However, the internal mechanisms of this pathogenic process are still unclear. Besides, the relationship among autophagy, apoptosis, and calcification in HASMCs upon AGEs exposure has not been reported in detail. In this study, we established a calcification model of SMC through the intervention of AGEs. It was found that the calcification was upregulated in AGEs treated HASMCs when autophagy and apoptosis were activated. In the country, AGEs-activated calcification and apoptosis were suppressed in Atg7 knockout cells or pretreated with wortmannin (WM), an autophagy inhibitor. These results provide new insights to conduct further investigations on the potential clinical applications for autophagy inhibitors in the treatment of diabetes-related vascular calcification.
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Affiliation(s)
- Hu-Qiang He
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.,Department of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yuan-Qing Qu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Betty Yuen Kwan Law
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Macau, China
| | - Cong-Ling Qiu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Yu Han
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Ivo Ricardo de Seabra Rodrigues Dias
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Yong Liu
- Department of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jie Zhang
- Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, China
| | - An-Guo Wu
- Laboratory of Chinese Materia Medical, School of Pharmacy, Southwest Medical University, Luzhou, China.,Institute of Cardiovascular Research, The Key Laboratory of Medical Electrophysiology, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Southwest Medical University, Luzhou, China
| | - Cheng-Wen Wu
- Department of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Simon Wing Fai Mok
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xin Cheng
- Department of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China.,Affiliated Hospital of Ya'an Polytechnic College, Ya'an, China
| | - Yan-Zheng He
- Department of Vascular Surgery, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Vincent Kam Wai Wong
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.,Guangdong-Hong Kong-Macau Joint Lab on Chinese Medicine and Immune Disease Research, Macau, China
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Yuan Y, He X, Li X, Liu Y, Tang Y, Deng H, Shi X. Narciclasine induces autophagy-mediated apoptosis in gastric cancer cells through the Akt/mTOR signaling pathway. BMC Pharmacol Toxicol 2021; 22:70. [PMID: 34753517 PMCID: PMC8579652 DOI: 10.1186/s40360-021-00537-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 10/29/2021] [Indexed: 12/27/2022] Open
Abstract
Background Gastric cancer is a common gastrointestinal cancer and currently has the third-highest mortality rate. Research shows that the natural compound narciclasine has a variety of biological activities. The present study aimed to investigate the effect of narciclasine on gastric cancer cells and its molecular mechanisms and determine whether this compound could be a novel therapy for gastric cancer. Methods MTT and clone assays were employed to detect the proliferation of gastric cancer cells. The cell apoptosis was detected by flow cytometry. The formation of autophagosomes and autophagosomal lysosomes was observed by transmission electron microscopy and laser confocal scanning microscopy. Western blotting was used to detect the expression of apoptosis, autophagy and Akt/mTOR pathway-related proteins. Results In this study, we found that narciclasine could inhibit the proliferation of gastric cancer cells and promote apoptosis in gastric cancer cells. Further experiments showed that narciclasine promoted the levels of autophagy proteins LC3-II, Atg-5 and Beclin-1, reduced the expression of the autophagy transporter p62, and increased autophagic flux. By using the autophagy inhibitors 3-MA and CQ, it was shown that narciclasine could induce autophagy-mediated apoptosis in gastric cancer cells. Finally, we found that narciclasine had no significant effects on the total content of Akt and mTOR in gastric cancer cells, and it involved autophagy in gastric cancer cells by reducing the phosphorylation level of p-Akt and p-mTOR. Conclusions Narciclasine can induce autophagy-dependent apoptosis in gastric cancer cells by inhibiting the phosphorylation level of Akt/mTOR and thus reduce the proliferation of gastric cancer cells.
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Affiliation(s)
- Yunfeng Yuan
- Department of Hepatobiliary Surgery, Chongqing Three Gorges Central Hospital, Chongqing University Three Gorges Hospital, No.165 Xincheng Road, Chongqing, 404000, China
| | - Xue He
- Department of Hepatobiliary Surgery, Chongqing Three Gorges Central Hospital, Chongqing University Three Gorges Hospital, No.165 Xincheng Road, Chongqing, 404000, China
| | - Xiang Li
- Department of Hepatobiliary Surgery, Chongqing Three Gorges Central Hospital, Chongqing University Three Gorges Hospital, No.165 Xincheng Road, Chongqing, 404000, China
| | - Yan Liu
- Department of Hepatobiliary Surgery, Chongqing Three Gorges Central Hospital, Chongqing University Three Gorges Hospital, No.165 Xincheng Road, Chongqing, 404000, China
| | - Yueliang Tang
- Department of General Surgery, Zengcheng District People's Hospital of Guangzhou, No.1 Guangming East Road, Guangzhou, 511300, China
| | - Huiming Deng
- Department of General Surgery, Zengcheng District People's Hospital of Guangzhou, No.1 Guangming East Road, Guangzhou, 511300, China.
| | - Xinyuan Shi
- Department of Gastroenterology, Taizhou First People's Hospital, No. 218 Hengjie Road, Taizhou, 318020, China.
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Fan P, Jordan VC. PERK, Beyond an Unfolded Protein Response Sensor in Estrogen-Induced Apoptosis in Endocrine-Resistant Breast Cancer. Mol Cancer Res 2021; 20:193-201. [PMID: 34728551 DOI: 10.1158/1541-7786.mcr-21-0702] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/04/2021] [Accepted: 10/28/2021] [Indexed: 11/16/2022]
Abstract
The discovery of 17β-estradiol (E2)-induced apoptosis has clinical relevance. Mechanistically, E2 over activates nuclear estrogen receptor α that results in stress responses. The unfolded protein response (UPR) is initiated by E2 in the endoplasmic reticulum after hours of treatment in endocrine-resistant breast cancer cells, thereby activating three UPR sensors-PRK-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6) with different functions. Specifically, PERK plays a critical role in induction of apoptosis whereas IRE1α and ATF6 are involved in the endoplasmic reticulum stress-associated degradation (ERAD) of PI3K/Akt/mTOR pathways. In addition to attenuating protein translation, PERK increases the DNA-binding activity of NF-κB and subsequent TNFα expression. In addition, PERK communicates with the mitochondria to regulate oxidative stress at mitochondria-associated endoplasmic reticulum membranes (MAM). Furthermore, PERK is a component enriched in MAMs that interacts with multifunctional MAM-tethering proteins and integrally modulates the exchange of metabolites such as lipids, reactive oxygen species (ROS), and Ca2+ at contact sites. MAMs are also critical sites for the initiation of autophagy to remove defective organelles and misfolded proteins through specific regulatory proteins. Thus, PERK conveys signals from nucleus to these membrane-structured organelles that form an interconnected network to regulate E2-induced apoptosis. Herein, we address the mechanistic progress on how PERK acts as a multifunctional molecule to commit E2 to inducing apoptosis in endocrine-resistant breast cancer.
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Affiliation(s)
- Ping Fan
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - V Craig Jordan
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Brix N, Samaga D, Belka C, Zitzelsberger H, Lauber K. Analysis of clonogenic growth in vitro. Nat Protoc 2021; 16:4963-4991. [PMID: 34697469 DOI: 10.1038/s41596-021-00615-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 08/10/2021] [Indexed: 02/08/2023]
Abstract
The clonogenic assay measures the capacity of single cells to form colonies in vitro. It is widely used to identify and quantify self-renewing mammalian cells derived from in vitro cultures as well as from ex vivo tissue preparations of different origins. Varying research questions and the heterogeneous growth requirements of individual cell model systems led to the development of several assay principles and formats that differ with regard to their conceptual setup, 2D or 3D culture conditions, optional cytotoxic treatments and subsequent mathematical analysis. The protocol presented here is based on the initial clonogenic assay protocol as developed by Puck and Marcus more than 60 years ago. It updates and extends the 2006 Nature Protocols article by Franken et al. It discusses different strategies and principles to analyze clonogenic growth in vitro and presents the clonogenic assay in a modular protocol framework enabling a diversity of formats and measures to optimize determination of clonogenic growth parameters. We put particular focus on the phenomenon of cellular cooperation and consideration of how this can affect the mathematical analysis of survival data. This protocol is applicable to any mammalian cell model system from which single-cell suspensions can be prepared and which contains at least a small fraction of cells with self-renewing capacity in vitro. Depending on the cell system used, the entire procedure takes ~2-10 weeks, with a total hands-on time of <20 h per biological replicate.
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Affiliation(s)
- Nikko Brix
- Department of Radiation Oncology, University Hospital, LMU München, Munich, Germany
| | - Daniel Samaga
- Research Unit Radiation Cytogenetics, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Neuherberg, Germany
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Neuherberg, Germany
| | - Claus Belka
- Department of Radiation Oncology, University Hospital, LMU München, Munich, Germany
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Neuherberg, Germany
- German Cancer Consortium (DKTK) partner site, Munich, Germany
| | - Horst Zitzelsberger
- Department of Radiation Oncology, University Hospital, LMU München, Munich, Germany
- Research Unit Radiation Cytogenetics, Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Neuherberg, Germany
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Neuherberg, Germany
| | - Kirsten Lauber
- Department of Radiation Oncology, University Hospital, LMU München, Munich, Germany.
- Clinical Cooperation Group 'Personalized Radiotherapy in Head and Neck Cancer', Helmholtz Center Munich, German Research Center for Environmental Health GmbH, Neuherberg, Germany.
- German Cancer Consortium (DKTK) partner site, Munich, Germany.
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The roles of GTPase-activating proteins in regulated cell death and tumor immunity. J Hematol Oncol 2021; 14:171. [PMID: 34663417 PMCID: PMC8524929 DOI: 10.1186/s13045-021-01184-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 09/27/2021] [Indexed: 12/22/2022] Open
Abstract
GTPase-activating protein (GAP) is a negative regulator of GTPase protein that is thought to promote the conversion of the active GTPase-GTP form to the GTPase-GDP form. Based on its ability to regulate GTPase proteins and other domains, GAPs are directly or indirectly involved in various cell requirement processes. We reviewed the existing evidence of GAPs regulating regulated cell death (RCD), mainly apoptosis and autophagy, as well as some novel RCDs, with particular attention to their association in diseases, especially cancer. We also considered that GAPs could affect tumor immunity and attempted to link GAPs, RCD and tumor immunity. A deeper understanding of the GAPs for regulating these processes could lead to the discovery of new therapeutic targets to avoid pathologic cell loss or to mediate cancer cell death.
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50
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Li C, Liu F, Yang X, Guo B, Li G, Yin J, He G, Yang C, Xu L, Li S, Wu H, Liu H, Ruan Y, Gu J, Wang L. Targeting lectin-like oxidized low-density lipoprotein receptor-1 triggers autophagic program in esophageal cancer. Cell Death Differ 2021; 29:697-708. [PMID: 34611296 DOI: 10.1038/s41418-021-00884-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/24/2021] [Accepted: 09/24/2021] [Indexed: 12/24/2022] Open
Abstract
Autophagy is a highly conserved catabolic process to maintain cellular homeostasis. However, dysfunctional autophagy contributes to a context-dependent role in cancer. Here, we clarified the exact role of autophagy modulated by the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in esophageal cancer (EC). A comprehensive analysis in various cancers displayed that LOX-1 was upregulated the most in EC tissues and associated with poor prognosis of patients. Deletion of LOX-1 ex vivo and in vivo suppresses EC development by inducing autophagic cell death. Receptor for activated C kinase 1 (RACK1) was identified as a signal adapter of LOX-1, which incented RAS/MEK/ERK pathway and TFEB nuclear export signal and safeguarded tumorigenesis. A sulfated polysaccharide fucoidan extracted from brown seaweed was found to bind with LOX-1 and mediate its proteasomal degradation but not the lysosome pathway, leading to autophagy-related cell death in EC. These results reveal a central contribution of LOX-1 to EC development and provide genetic ablation or bioactive polysaccharide as an effective intervention for EC therapy.
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Affiliation(s)
- Can Li
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Fenglin Liu
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 20032, China
| | - Xu Yang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Bao Guo
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Guoyun Li
- Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Laboratory for Marine Drugs and Bioproducts, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao, 266237, China
| | - Jie Yin
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 20032, China
| | - Gaofei He
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Caiting Yang
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Ling Xu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Shuxuan Li
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Hao Wu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Hai Liu
- Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China
| | - Yuanyuan Ruan
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Jianxin Gu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China
| | - Lan Wang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
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