PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion

M. Cecilia Caino, Jagadish C. Ghosh, Young Chan Chae, Valentina Vaira, Dayana B. Rivadeneira, Alice Faversani, Paolo Rampini, Andrew V. Kossenkov, Katherine M. Aird, Rugang Zhang, Marie R. Webster, Ashani T. Weeraratna, Silvano Bosari, Lucia R. Languino, Dario C. Altieri

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87 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8638-8643
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number28
DOIs
StatePublished - Jul 14 2015

All Science Journal Classification (ASJC) codes

  • General

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    Caino, M. C., Ghosh, J. C., Chae, Y. C., Vaira, V., Rivadeneira, D. B., Faversani, A., Rampini, P., Kossenkov, A. V., Aird, K. M., Zhang, R., Webster, M. R., Weeraratna, A. T., Bosari, S., Languino, L. R., & Altieri, D. C. (2015). PI3K therapy reprograms mitochondrial trafficking to fuel tumor cell invasion. Proceedings of the National Academy of Sciences of the United States of America, 112(28), 8638-8643. https://doi.org/10.1073/pnas.1500722112