Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming

Young Chan Chae, Valentina Vaira, M. Cecilia Caino, Hsin Yao Tang, Jae Ho Seo, Andrew V. Kossenkov, Luisa Ottobrini, Cristina Martelli, Giovanni Lucignani, Irene Bertolini, Marco Locatelli, Kelly G. Bryant, Jagadish C. Ghosh, Sofia Lisanti, Bonsu Ku, Silvano Bosari, Lucia R. Languino, David W. Speicher, Dario C. Altieri

Research output: Contribution to journalArticle

Abstract

Hypoxia is a universal driver of aggressive tumor behavior, but the underlying mechanisms are not completely understood. Using a phosphoproteomics screen, we now show that active Akt accumulates in the mitochondria during hypoxia and phosphorylates pyruvate dehydrogenase kinase 1 (PDK1) on Thr346 to inactivate the pyruvate dehydrogenase complex. In turn, this pathway switches tumor metabolism toward glycolysis, antagonizes apoptosis and autophagy, dampens oxidative stress, and maintains tumor cell proliferation in the face of severe hypoxia. Mitochondrial Akt-PDK1 signaling correlates with unfavorable prognostic markers and shorter survival in glioma patients and may provide an “actionable” therapeutic target in cancer.

Original languageEnglish
Pages (from-to)257-272
Number of pages16
JournalCancer Cell
Volume30
Issue number2
DOIs
Publication statusPublished - Aug 8 2016

Keywords

  • Akt
  • hypoxia
  • metabolism
  • mitochondria
  • PDK1
  • tumor cell proliferation

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Chae, Y. C., Vaira, V., Caino, M. C., Tang, H. Y., Seo, J. H., Kossenkov, A. V., Ottobrini, L., Martelli, C., Lucignani, G., Bertolini, I., Locatelli, M., Bryant, K. G., Ghosh, J. C., Lisanti, S., Ku, B., Bosari, S., Languino, L. R., Speicher, D. W., & Altieri, D. C. (2016). Mitochondrial Akt Regulation of Hypoxic Tumor Reprogramming. Cancer Cell, 30(2), 257-272. https://doi.org/10.1016/j.ccell.2016.07.004