Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes.

Activating KRAS mutations are important for cancer initiation and progression; and have recently been shown to cause primary resistance to therapies targeting the epidermal growth factor receptor. Therefore, strategies are currently in development to overcome treatment resistance due to oncogenic KRAS. The hypoxia-inducible factors-1α and -2α (HIF-1α and HIF-2α) are activated in cancer due to dysregulated ras signaling. To understand the individual and combined roles of HIF-1α and HIF-2α in cancer metabolism and oncogenic KRAS signaling, we used targeted homologous recombination to disrupt the oncogenic KRAS, HIF-1α, and HIF-2α gene loci in HCT116 colon cancer cells to generate isogenic HCT116WT KRAS, HCT116HIF-1α-/-, HCT116HIF-2α-/-, and HCT116HIF-1α-/-HIF-2α-/- cell lines. Global gene expression analyses of these cell lines reveal that HIF-1α and HIF-2α work together to modulate cancer metabolism and regulate genes signature overlapping with oncogenic KRAS. Cancer cells with disruption of both HIF-1α and HIF-2α or oncogenic KRAS showed decreased aerobic respiration and ATP production, with increased ROS generation. Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations.

激活型KRAS突变对癌症的发生和进展至关重要；并且最近已被证明会导致对表皮生长因子受体靶向治疗产生原发性耐药。因此，目前正在开发一些策略来克服由致癌KRAS导致的治疗耐药性。由于ras信号失调，缺氧诱导因子 -1α和 -2α（HIF -1α和HIF -2α）在癌症中被激活。 为了了解HIF -1α和HIF -2α在癌症代谢和致癌KRAS信号传导中的单独及联合作用，我们利用靶向同源重组技术破坏HCT116结肠癌细胞中的致癌KRAS、HIF -1α和HIF -2α基因位点，以产生同基因的HCT116野生型KRAS、HCT116 HIF -1α -/-、HCT116 HIF -2α -/-以及HCT116 HIF -1α -/- HIF -2α -/-细胞系。 对这些细胞系的全基因表达分析表明，HIF -1α和HIF -2α共同作用以调节癌症代谢，并调控与致癌KRAS重叠的基因特征。HIF -1α和HIF -2α两者均被破坏的癌细胞或者致癌KRAS被破坏的癌细胞显示有氧呼吸和ATP产生减少，同时活性氧（ROS）生成增加。 我们的研究结果为治疗具有致癌KRAS突变的肿瘤提出了新的策略。