Research Paper Volume 16, Issue 3 pp 2679—2701
Underlying mechanisms of novel cuproptosis-related dihydrolipoamide branched-chain transacylase E2 (DBT) signature in sunitinib-resistant clear-cell renal cell carcinoma
- 1 Division of Hematology/Oncology, Department of Internal Medicine, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan
- 2 Department of Orthopaedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 3 Department of Orthopaedics, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- 4 Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan
- 5 Department of Medical Research, Taipei Medical University Shuang-Ho Hospital, Taipei, Taiwan
- 6 Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung, Taiwan
- 7 Department of Dentistry, Taipei Medical University-Shuang Ho Hospital, New Taipei City, Taiwan
- 8 School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City, Taiwan
- 9 Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- 10 Taipei Medical University-Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan
- 11 Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan
- 12 Division of Nephrology, Department of Internal Medicine, Hsin Kuo Min Hospital, Taipei Medical University, Taoyuan City, Taiwan
Received: May 23, 2023 Accepted: November 30, 2023 Published: February 1, 2024
https://doi.org/10.18632/aging.205504How to Cite
Copyright: © 2024 Lai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Renal cell carcinoma (RCC) is the predominant form of malignant kidney cancer. Sunitinib, a primary treatment for advanced, inoperable, recurrent, or metastatic RCC, has shown effectiveness in some patients but is increasingly limited by drug resistance. Recently identified cuproptosis, a copper-ion-dependent form of programmed cell death, holds promise in combating cancer, particularly drug-resistant types. However, its effectiveness in treating drug resistant RCC remains to be determined. Exploring cuproptosis's regulatory mechanisms could enhance RCC treatment strategies. Our analysis of data from the GEO and TCGA databases showed that the cuproptosis-related gene DBT is markedly under expressed in RCC tissues, correlating with worse prognosis and disease progression. In our study, we investigated copper CRGs in ccRCC, noting substantial expression differences, particularly in advanced-stage tumors. We established a connection between CRG expression levels and patient survival, positioning CRGs as potential therapeutic targets for ccRCC. In drug resistant RCC cases, we found distinct expression patterns for DBT and GLS CRGs, linked to treatment resistance. Our experiments demonstrated that increasing DBT expression significantly reduces RCC cell growth and spread, underscoring its potential as a therapeutic target. This research sheds new light on the role of CRGs in ccRCC and their impact on drug resistance.
Abbreviations
Atox1: antioxidant-1; DLAT: dihydrolipoyllysine-residue acetyltransferase; DBT: dihydrolipoamide branched-chain transacylase E2; RCC: Renal cell carcinoma; CKD: chronic kidney disease; ccRCC: clear-cell RCC; pRCC: papillary RCC; chRCC: chromophobe RCC; MAPLK: mitogen-activated protein kinase; VEGF: vascular endothelial growth factor; TKIs: tyrosine kinase inhibitors; TNM: tumor, node, and metastasis.