Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition.
Oxidative stress downstream of mTORC1 but not AKT causes a proliferative defect in cancer cells resistant to PI3K inhibition.
复制标题
DOI：
10.1038/onc.2016.435
复制
发表时间：
2017-05-11
期刊：
影响因子：
8
通讯作者：
Cutillas PR
中科院分区：
文献类型：
--
作者：
Dermit M;Casado P;Rajeeve V;Wilkes EH;Foxler DE;Campbell H;Critchlow S;Sharp TV;Gribben JG;Unwin R;Cutillas PR
靶向磷脂酰肌醇-3-激酶/哺乳动物雷帕霉素靶点（PI 3 K/mTOR）信号传导的化合物正在多个临床环境中进行研究，但耐药性可能会降低其益处。药物假期后的化合物再激发可以克服这种阻力，但对药物假期对细胞生物化学的影响知之甚少。我们发现，在没有PI 3 Ki的情况下培养的PI 3 K抑制剂（PI 3 Ki）抗性细胞出现增殖缺陷，增加氧消耗和积累活性氧（ROS），导致通过缺氧诱导因子-1 α产生乳酸。这种代谢失衡被雷帕霉素复合物1（mTORC 1）抑制剂的哺乳动物靶逆转。有趣的是，AKT和c-MYC都不参与介导代谢表型，尽管后者有助于抗性细胞的增殖。这些数据表明，AKT-独立的PI 3 K/mTORC 1轴在这些细胞中运作。过量的ROS阻碍细胞分裂，代谢表型使抗性细胞对过氧化氢和营养饥饿更敏感。因此，药物假期期间PI 3 K-抗性细胞的增殖缺陷是由对慢性PI 3 K/mTOR途径抑制的代谢适应缺陷引起的。这种代谢失衡可能会打开治疗窗口，在药物假期期间使用代谢药物进行挑战。
Compounds targeting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling are being investigated in multiple clinical settings, but drug resistance may reduce their benefit. Compound rechallenge after drug holidays can overcome such resistance, yet little is known about the impact of drug holidays on cell biochemistry. We found that PI3K inhibitor (PI3Ki)-resistant cells cultured in the absence of PI3Ki developed a proliferative defect, increased oxygen consumption and accumulated reactive oxygen species (ROS), leading to lactate production through hypoxia-inducible factor-1α. This metabolic imbalance was reversed by mammalian target of rapamycin complex 1 (mTORC1) inhibitors. Interestingly, neither AKT nor c-MYC was involved in mediating the metabolic phenotype, despite the latter contributing to resistant cells' proliferation. These data suggest that an AKT-independent PI3K/mTORC1 axis operates in these cells. The excessive ROS hampered cell division, and the metabolic phenotype made resistant cells more sensitive to hydrogen peroxide and nutrient starvation. Thus, the proliferative defect of PI3Ki-resistant cells during drug holidays is caused by defective metabolic adaptation to chronic PI3K/mTOR pathway inhibition. This metabolic imbalance may open the therapeutic window for challenge with metabolic drugs during drug holidays.