Ran Jialing, Li Feifei, Zhan Lei, Jin Yue, Dong Qian, Li Xiaoyan, Li XiaoXi, Fei Qian, Zhang Jingdong
Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, PR China.
Shengjing Hospital of China Medical University, PR China.
J Cancer. 2025 Apr 28;16(8):2503-2515. doi: 10.7150/jca.108582. eCollection 2025.
Oxaliplatin (L-OHP) is a first-line chemotherapy agent for advanced colorectal cancer (CRC), but the development of resistance often compromises its efficacy. Tumor hypoxia and metabolic reprogramming are known to influence chemotherapy sensitivity, yet their interrelationship remains inadequately explored. assays were conducted using human colorectal cancer cell lines (DLD1 and LoVo) under hypoxic conditions induced by cobalt chloride (CoCl2). The expression levels of key proteins involved in the HIF-1α/BMAL1/ALDOC pathway were assessed through Western blotting and quantitative real-time PCR (qPCR). Cell viability, apoptosis, and glycolytic activity were evaluated using CCK-8 assays, flow cytometry, and lactate/ATP measurements. Hypoxia significantly enhanced glycolysis in CRC cells, decreasing sensitivity to L-OHP. The HIF-1α/BMAL1/ALDOC axis was identified as a crucial mediator in this process, with HIF-1α upregulating BMAL1, which increased ALDOC expression. This cascade promoted glycolytic activity and reduced apoptosis in hypoxic conditions. Notably, a positive correlation between HIF-1α and ALDOC expression was confirmed in clinical CRC samples. The findings reveal a novel mechanism by which hypoxia diminishes L-OHP sensitivity in CRC through the HIF-1α/BMAL1/ALDOC pathway. These insights provide potential biomarkers for predicting treatment outcomes and suggest new therapeutic strategies to enhance chemosensitivity in colorectal cancer.
奥沙利铂（L-OHP）是晚期结直肠癌（CRC）的一线化疗药物，但耐药性的产生常常会削弱其疗效。已知肿瘤缺氧和代谢重编程会影响化疗敏感性，但其相互关系仍未得到充分探索。在氯化钴（CoCl2）诱导的缺氧条件下，使用人结肠癌细胞系（DLD1和LoVo）进行了实验。通过蛋白质免疫印迹法和定量实时聚合酶链反应（qPCR）评估了HIF-1α/BMAL1/ALDOC途径中关键蛋白的表达水平。使用CCK-8检测法、流式细胞术以及乳酸/三磷酸腺苷（ATP）测量评估细胞活力、细胞凋亡和糖酵解活性。缺氧显著增强了CRC细胞中的糖酵解，降低了对L-OHP的敏感性。HIF-1α/BMAL1/ALDOC轴被确定为这一过程中的关键介质，其中HIF-1α上调BMAL1，进而增加ALDOC的表达。这一级联反应在缺氧条件下促进了糖酵解活性并减少了细胞凋亡。值得注意的是，在临床CRC样本中证实了HIF-1α与ALDOC表达之间呈正相关。这些发现揭示了一种新机制，即缺氧通过HIF-1α/BMAL1/ALDOC途径降低CRC对L-OHP的敏感性。这些见解为预测治疗结果提供了潜在的生物标志物，并提出了增强结直肠癌化疗敏感性的新治疗策略。
