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ORIGINAL RESEARCH article

Front. Oncol.

Sec. Gastrointestinal Cancers: Colorectal Cancer

Volume 15 - 2025 | doi: 10.3389/fonc.2025.1625797

This article is part of the Research TopicNavigating Drug Resistance in Solid Tumors: Biomarkers, Metabolism, and Immune-Based TherapiesView all articles

Multiomics Analyses of Human Colorectal Cancer Reveal Changes in Mitochondrial Metabolism Associated with Chemotherapy Resistance

Provisionally accepted
WEI  ZHENGWEI ZHENG1*Shiyi  ChenShiyi Chen2Qian  LiQian Li1
  • 1Department of Pathology, Zhongshan Hospital, Xiamen University, Xiamen, China
  • 2School of Medicine, Xiamen University, Xiamen, China

The final, formatted version of the article will be published soon.

Background: Mitochondria are essential organelles involved in energy production, cellular metabolism, and signal transduction. They have important impacts on tumorigenesis and cancer progression. Nevertheless, the associations between mitochondrial metabolic processes and chemotherapy resistance in colorectal cancer (CRC) are not well understood. Methods: We generated a chemotherapy-resistant colorectal cancer cell line, HCT-15/DOX, via doxorubicin (DOX) induction. We then performed proteomic and metabolomic analyses via LC-MS/MS technology on both the parental and the DOX-resistant cell lines. Additionally, transmission electron microscopy was used to examine changes in mitochondrial morphology between the two cell lines. Results: The results revealed significant dysregulation of 185 proteins and 1099 metabolites in HCT-15/DOX cells relative to parental cells, highlighting the impact of chemotherapy resistance on cellular processes. The key functional proteins that were identified included upregulated SDHA, BCKDHB, CRYZ, NUDT6, CPT1A, and POLG, and downregulated CRAT, FDPS, SFXN1, and ATAD3B. Additionally, through combined multiomics pathway enrichment analysis, pyrimidine metabolism, purine metabolism, ascorbate and aldarate metabolism, propanoate metabolism, and the citrate cycle (TCA cycle) were identified as important metabolic processes associated with CRC chemotherapy resistance. Transmission electron microscopy analysis revealed that HCT-15/DOX cells had increased mitochondrial number, length, and area. Conclusions: This research highlights notable differences in mitochondrial morphology and diverse mitochondrial metabolic functions between parental and DOX-resistant HCT-15 CRC cells. The findings of the present study provide insights into the mitochondrial metabolic changes associated with CRC chemotherapy resistance, offering valuable insights into the mechanisms underlying these changes and identifying potential therapeutic targets for addressing CRC chemotherapy resistance.

Keywords: Proteomics, Metabolomics, colorectal cancer, chemotherapy resistance, mitochondrial metabolism

Received: 09 May 2025; Accepted: 22 Oct 2025.

Copyright: © 2025 ZHENG, Chen and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: WEI ZHENG, zhengwei@xmu.edu.cn

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