Protein phosphatase 2A and DNA-dependent protein kinase are involved in mediating rapamycin-induced Akt phosphorylation.

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Protein phosphatase 2A and DNA-dependent protein kinase are involved in mediating rapamycin-induced Akt phosphorylation.

J Biol Chem. 2013 Mar 27;

Authors: Li Y, Wang X, Yue P, Tao H, Ramalingam SS, Owonikoko TK, Deng X, Wang Y, Fu H, Khuri FR, Sun SY

Abstract
Inhibition of mammalian target of rapamycin complex 1 (mTORC1), for example with rapamycin, increases Akt phosphorylation while inhibiting mTORC1 signaling. However the underlying mechanisms have not been fully elucidated. The current study has uncovered a previously unknown mechanism underlying rapamycin induced Akt phosphorylation involving protein phosphatase 2A (PP2A) dependent DNA protein kinase (DNA-PK) activation. In several cancer cell lines, inhibition of PP2A with okadaic acid, fostriecin, small T antigen, or PP2A knockdown abrogated rapamycin induced Akt phosphorylation, and rapamycin increased PP2A activity. Chemical inhibition of DNA-PK, knockdown or deficiency of DNA-PK catalytic subunit (DNA-PKcs), or knockout of the DNA-PK component Ku86 inhibited rapamycin induced Akt phosphorylation. Exposure of cancer cells to rapamycin increased DNA-PK activity and gene silencing mediated PP2A inhibition attenuated rapamycin-induced DNA-PK activity. Collectively these results suggest that rapamycin induces PP2A dependent and DNA-PK mediated Akt phosphorylation. Accordingly, simultaneous inhibition of mTOR and DNA-PK did not stimulate Akt activity and synergistically inhibited the growth of cancer cells both in vitro and in vivo. Thus, our findings also suggest a novel strategy to enhance mTOR targeted cancer therapy by cotargeting DNA-PK.

PMID: 23536185 [PubMed - as supplied by publisher]

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