Ma JX, Li XJ, Li YL, Liu MC, Du RH, Cheng Y, Li LJ, Ai ZY, Jiang JT, Yan SY. Chaperonin-containing tailless complex polypeptide 1 subunit 6A negatively regulates autophagy and protects colorectal cancer cells from cisplatin-induced cytotoxicity. World J Gastroenterol 2025; 31(18): 105729 [DOI: 10.3748/wjg.v31.i18.105729]
Corresponding Author of This Article
Si-Yuan Yan, PhD, Associate Professor, Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, No. 133 Hehua Road, Jining 272067, Shandong Province, China. yansy@mail.jnmc.edu.cn
Research Domain of This Article
Cell Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. May 14, 2025; 31(18): 105729 Published online May 14, 2025. doi: 10.3748/wjg.v31.i18.105729
Chaperonin-containing tailless complex polypeptide 1 subunit 6A negatively regulates autophagy and protects colorectal cancer cells from cisplatin-induced cytotoxicity
Jian-Xing Ma, Xiao-Jun Li, Ya-Long Li, Ming-Chan Liu, Rui-Hang Du, Yi Cheng, Liang-Jie Li, Zhi-Ying Ai, Jian-Tao Jiang, Si-Yuan Yan
Jian-Xing Ma, Ming-Chan Liu, Rui-Hang Du, Yi Cheng, Liang-Jie Li, Zhi-Ying Ai, Si-Yuan Yan, Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, Jining 272067, Shandong Province, China
Xiao-Jun Li, Ya-Long Li, Department of General Surgery, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
Jian-Tao Jiang, The Second Affiliated Hospital of Xi’an Jiaotong University, Xibei Hospital, Xi’an 710000, Shaanxi Province, China
Co-corresponding authors: Jian-Tao Jiang and Si-Yuan Yan.
Author contributions: Ma JX contributed to the methodology, validation, formal analysis, and investigation; Li XJ, Li YL, Liu MC, Cheng Y, and Li LJ contributed to the investigation; Du RH performed the investigation involving the use of software; Ai ZY helped to review and improve the manuscript. Jiang JT and Yan SY played important and indispensable roles in the experimental design, data interpretation, and manuscript preparation as the co-corresponding authors.
Supported by Shandong Provincial Natural Science Foundation, No. ZR2023MH329; Project of Shandong Province Higher Educational Youth Innovation Science and Technology Program, No. 2023KJ263; and Natural Science Foundation of Gansu Province, China, No. 22JR5RA953.
Institutional review board statement: This research undertaking excludes animal experiments and human tissue usage, relying instead on commercialized colorectal cancer cell lines, thereby obviating the need for submitting relevant ethical review documentation.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: Data will be made available on request at yansy@mail.jnmc.edu.cn.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Si-Yuan Yan, PhD, Associate Professor, Precision Medicine Laboratory for Chronic Non-communicable Diseases of Shandong Province, Institute of Precision Medicine, Jining Medical University, No. 133 Hehua Road, Jining 272067, Shandong Province, China. yansy@mail.jnmc.edu.cn
Received: February 5, 2025 Revised: March 27, 2025 Accepted: April 14, 2025 Published online: May 14, 2025 Processing time: 97 Days and 18.1 Hours
Abstract
BACKGROUND
As a member of the chaperonin-containing tailless complex polypeptide 1 (TCP1) complex, which plays a pivotal role in ensuring the accurate folding of numerous proteins, chaperonin-containing TCP1 subunit 6A (CCT6A) participates in various physiological and pathological processes. However, its effects on cell death and cancer therapy and the underlying mechanisms need further exploration in colorectal cancer (CRC) cells.
AIM
To explore the effects of CCT6A on cell death and cancer therapy and the underlying mechanisms in CRC.
METHODS
Cell proliferation was evaluated using the MTS assay, EdU staining, and colony growth assays. The expression of CCT6A was monitored by immunoblotting and quantitative PCR. CCT6A was knocked out by CRISPR-Cas9, and overexpressed by transfecting plasmids. Autophagy was examined by immunoblotting and the mCherry-GFP-LC3 assay. To monitor apoptosis and necroptosis, immunoblotting, co-immunoprecipitation, and flow cytometry were employed.
RESULTS
Cisplatin (DDP) exerted cytotoxic effects on CRC cells while simultaneously downregulating the expression of CCT6A. Depletion of CCT6A amplified the cytotoxic effects of DDP, whereas overexpression of CCT6A attenuated these adverse effects. CCT6A suppressed autophagy, apoptosis, and necroptosis under both basal and DDP-treated conditions. Autophagy inhibitors significantly enhanced the cytotoxic effects of DDP, whereas a necroptosis inhibitor partially reversed the cell viability loss induced by DDP. Furthermore, inhibiting autophagy enhanced both apoptosis and necroptosis induced by DDP.
CONCLUSION
CCT6A negatively modulates autophagy, apoptosis, and necroptosis, and CCT6A confers resistance to DDP therapy in CRC, suggesting its potential as a therapeutic target.
Core Tip: This study evaluated the role of chaperonin-containing tailless complex polypeptide 1 subunit 6A (CCT6A) in colorectal cancer (CRC) therapy. CCT6A expression was downregulated by cisplatin (DDP) in CRC cells, enhancing its cytotoxicity. Depletion of CCT6A potentiated DDP's effects by promoting autophagy, apoptosis, and necroptosis, whereas its overexpression provided resistance. Immunoblotting and autophagy confirmed CCT6A's negative regulatory role in autophagy. Markers of apoptosis and necroptosis were upregulated in CCT6A-depleted cells, indicating increased cell death. Autophagy inhibition exacerbated cell death, compromising viability and proliferation. Thus, CCT6A is a potential therapeutic target in CRC, modulating key cellular processes and enhancing DDP efficacy.
