Hypoxia regulates glycolysis through the HIF-1α/BMAL1/ALDOC axis to reduce oxaliplatin sensitivity in colorectal cancer.

Abstract

Background: 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. Methods: In vitro 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. Results: 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. Conclusion: 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.