Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute of Health (BIH), Robert-Roessle-Str. 10, 13125, Berlin, Germany.
Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin Institute for Medical Systems Biology (BIMSB), Robert-Roessle-Str. 10, 13125, Berlin, Germany.
Sci Rep. 2018 Jun 15;8(1):9204. doi: 10.1038/s41598-018-27394-1.
Metabolic reprogramming is as a hallmark of cancer, and several studies have reported that BRAF and KRAS tumors may be accompanied by a deregulation of cellular metabolism. We investigated how BRAF and KRAS affect cell metabolism, stress resistance and signaling in colorectal carcinoma cells driven by these mutations. KRAS expressing cells are characterized by the induction of glycolysis, accumulation of lactic acid and sensitivity to glycolytic inhibition. Notably mathematical modelling confirmed the critical role of MCT1 designating the survival of KRAS cells. Carcinoma cells harboring BRAF remain resistant towards alterations of glucose supply or application of signaling or metabolic inhibitors. Altogether these data demonstrate that an oncogene-specific decoupling of mTOR from AMPK or AKT signaling accounts for alterations of resistance mechanisms and metabolic phenotypes. Indeed the inhibition of mTOR in BRAF cells counteracts the metabolic predisposition and demonstrates mTOR as a potential target in BRAF-driven colorectal carcinomas.
代谢重编程是癌症的一个标志，有几项研究报道称，BRAF 和 KRAS 肿瘤可能伴随着细胞代谢的失调。我们研究了 BRAF 和 KRAS 如何影响这些突变驱动的结直肠癌细胞的细胞代谢、应激抵抗和信号转导。表达 KRAS 的细胞的特征是糖酵解的诱导、乳酸的积累和对糖酵解抑制的敏感性。值得注意的是，数学建模证实了 MCT1 指定 KRAS 细胞存活的关键作用。携带 BRAF 的癌细胞仍然对葡萄糖供应的改变或信号或代谢抑制剂的应用具有抗性。总的来说，这些数据表明，mTOR 与 AMPK 或 AKT 信号的特定致癌基因脱耦解释了耐药机制和代谢表型的改变。事实上，在 BRAF 细胞中抑制 mTOR 可以逆转代谢倾向，并表明 mTOR 是 BRAF 驱动的结直肠癌的一个潜在靶点。
