期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 28, 页码 8638-8643出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1500722112
关键词
mitochondria; molecular therapy; cytoskeleton; PI3K; cell invasion
资金
- National Institutes of Health [P01 CA140043, R01 CA78810, CA190027, F32 CA177018, R01 CA089720]
- Office of the Assistant Secretary of Defense for Health Affairs through the Prostate Cancer Research Program [W81XWH-13-1-0193]
- Fondazione IRCCS Ca' Granda
- Istituto Nazionale Genetica Molecolare
- Cancer Center Support Grant [CA010815]
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.
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