Table 6_Multiomics analyses of human colorectal cancer reveal changes in mitochondrial metabolism associated with chemotherapy resistance.xls

BackgroundMitochondria 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.
MethodsWe 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.
ResultsThe 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.
ConclusionsThis 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.

背景 线粒体（Mitochondria）是参与能量产生、细胞代谢及信号转导的重要细胞器，其在肿瘤发生与癌症进展中发挥关键作用。然而，结直肠癌（colorectal cancer, CRC）中线粒体代谢过程与化疗耐药之间的关联尚未得到充分阐释。
方法 本研究通过阿霉素（doxorubicin, DOX）诱导构建了结直肠癌化疗耐药细胞系HCT-15/DOX。随后，本研究采用液相色谱-串联质谱（liquid chromatography-tandem mass spectrometry, LC-MS/MS）技术对亲本细胞系与DOX耐药细胞系分别开展蛋白质组学与代谢组学分析。此外，本研究借助透射电子显微镜观察两种细胞系的线粒体形态变化。
结果 与亲本细胞相比，HCT-15/DOX细胞中共检测到185个蛋白质与1099个代谢物存在显著表达失调，凸显了化疗耐药对细胞进程的影响。本研究鉴定到的关键功能蛋白包括上调表达的SDHA、BCKDHB、CRYZ、NUDT6、CPT1A及POLG，以及下调表达的CRAT、FDPS、SFXN1与ATAD3B。此外，通过多组学通路富集联合分析，本研究明确嘧啶代谢、嘌呤代谢、抗坏血酸与醛糖酸代谢、丙酸代谢以及三羧酸循环（citrate cycle, TCA cycle）为与结直肠癌化疗耐药相关的重要代谢过程。透射电子显微镜观察结果显示，HCT-15/DOX细胞的线粒体数量、长度与面积均显著升高。
结论 本研究揭示了结直肠癌亲本HCT-15细胞与DOX耐药HCT-15细胞在线粒体形态及多样的线粒体代谢功能上存在显著差异。本研究结果为阐明结直肠癌化疗耐药相关的线粒体代谢变化提供了全新视角，深入解析了此类变化的潜在机制，并为破解结直肠癌化疗耐药难题找到了潜在治疗靶点。