The PI3K/Akt pathway regulates oxygen metabolism via pyruvate dehydrogenase (PDH)-E1α phosphorylation

George J. Cerniglia, Souvik Dey, Shannon M. Gallagher-Colombo, Natalie A. Daurio, Stephen Tuttle, Theresa M. Busch, Alexander Lin, Ramon Sun, Tatiana V. Esipova, Sergei A. Vinogradov, Nicholas Denko, Constantinos Koumenis, Amit Maity

Research output: Contribution to journalArticlepeer-review

51 Scopus citations

Abstract

Inhibition of the PI3K/Akt pathway decreases hypoxia within SQ20B human head and neck cancer xenografts. We set out to understand the molecular mechanism underlying this observation. We measured oxygen consumption using both a Clark electrode and an extracellular flux analyzer. We made these measurements after various pharmacologic and genetic manipulations. Pharmacologic inhibition of the PI3K/mTOR pathway or genetic inhibition of Akt/PI3K decreased the oxygen consumption rate (OCR) in vitro in SQ20B and other cell lines by 30% to 40%. Pharmacologic inhibition of this pathway increased phosphorylation of the E1a subunit of the pyruvate dehydrogenase (PDH) complex on Ser293, which inhibits activity of this critical gatekeeper of mitochondrial respiration. Expressing wild-type PTEN in a doxycycline-inducible manner in a cell line with mutant PTEN led to an increase in PDH-E1α phosphorylation and a decrease in OCR. Pretreatment of SQ20B cells with dichloroacetate (DCA), which inhibits PDH-E1α phosphorylation by inhibiting dehydrogenase kinases (PDK), reversed the decrease in OCR in response to PI3K/Akt/mTOR inhibition. Likewise, introduction of exogenous PDH-E1α that contains serine to alanine mutations, which can no longer be regulated by phosphorylation, also blunted the decrease in OCR seen with PI3K/mTOR inhibition. Our findings highlight an association between the PI3K/mTOR pathway and tumor cell oxygen consumption that is regulated in part by PDH phosphorylation. These results have important implications for understanding the effects of PI3K pathway activation in tumor metabolism and also in designing cancer therapy trials that use inhibitors of this pathway.

Original languageEnglish
Pages (from-to)1928-1938
Number of pages11
JournalMolecular Cancer Therapeutics
Volume14
Issue number8
DOIs
StatePublished - Aug 1 2015

Bibliographical note

Publisher Copyright:
©2015 AACR.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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