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BACKGROUND
The mechanisms underlying rapamycin-induced Akt phosphorylation have not been fully elucidated.RESULTS
Inhibition of PP2A or DNA-PK attenuates or abrogates rapamycin-induced Akt phosphorylation and co-inhibition of mTOR and DNA-PK enhances anticancer activity.CONCLUSIONS
PP2A-dependent and DNA-PK-mediated mechanism is involved in rapamycin-induced Akt phosphorylation.CONCLUSIONS
A previously unknown mechanism underlying rapamycin-induced Akt phosphorylation and a novel strategy to enhance mTOR-targeted cancer therapy may be suggested. 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 knock-out 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 co-targeting DNA-PK.
DNA protein kinase (DNA-PK) → phosphatase 2A (PP2A): " 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 "
Akt → DNA-PK: " Chemical inhibition of DNA-PK , knockdown or deficiency of DNA-PK catalytic subunit (DNA-PKcs), or knock-out of the DNA-PK component Ku86 inhibited rapamycin induced Akt phosphorylation "
DNA-PK ⊣ PP2A: " Exposure of cancer cells to rapamycin increased DNA-PK activity, and gene silencing mediated PP2A inhibition attenuated rapamycin induced DNA-PK activity "
Akt → PP2A: " Collectively these results suggest that rapamycin induces PP2A dependent and DNA-PK mediated Akt phosphorylation "
Akt ⊣ DNA-PK: " 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 "
Akt ⊣ mTOR: " 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 "