PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion
PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion
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DOI：
10.1073/pnas.1500722112
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发表时间：
2015-07-14
影响因子：
11.1
通讯作者：
Altieri, Dario C.
中科院分区：
文献类型：
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作者：
Caino, M. Cecilia;Ghosh, Jagadish C.;Altieri, Dario C.
分子疗法是“个性化”医学的标志，但肿瘤如何适应这些药物尚不清楚。在这里，我们表明，目前在临床上的磷脂酰肌醇3-激酶（PI 3 K）的小分子抑制剂诱导肿瘤中的全球转录重编程，激活生长因子受体，Akt和哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化，并增加肿瘤细胞的运动性和侵袭性。这种反应涉及重新分配的积极活跃的线粒体皮质细胞骨架，在那里他们支持膜动力学，营业额的粘着斑复合物，和随机细胞运动。阻断氧化磷酸化可阻止线粒体的适应性运输，损害膜动力学，并抑制肿瘤细胞的侵袭。因此，“时空”线粒体呼吸适应性诱导PI 3 K治疗燃料肿瘤细胞的侵袭，并可能提供一个重要的抗转移的目标。
Molecular therapies are hallmarks of "personalized" medicine, but how tumors adapt to these agents is not well-understood. Here we show that small-molecule inhibitors of phosphatidylinositol 3-kinase (PI3K) currently in the clinic induce global transcriptional reprogramming in tumors, with activation of growth factor receptors, (re)phosphorylation of Akt and mammalian target of rapamycin (mTOR), and increased tumor cell motility and invasion. This response involves redistribution of energetically active mitochondria to the cortical cytoskeleton, where they support membrane dynamics, turnover of focal adhesion complexes, and random cell motility. Blocking oxidative phosphorylation prevents adaptive mitochondrial trafficking, impairs membrane dynamics, and suppresses tumor cell invasion. Therefore, "spatiotemporal" mitochondrial respiration adaptively induced by PI3K therapy fuels tumor cell invasion, and may provide an important antimetastatic target.