Format

Send to

Choose Destination
See comment in PubMed Commons below
J Biol Chem. 2013 May 10;288(19):13215-24. doi: 10.1074/jbc.M113.463679. Epub 2013 Mar 27.

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

Author information

1
Departments of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, Georgia 30322, USA.

Abstract

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.

CONCLUSION:

PP2A-dependent and DNA-PK-mediated mechanism is involved in rapamycin-induced Akt phosphorylation.

SIGNIFICANCE:

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.

KEYWORDS:

Akt; Cancer Biology; Cancer Therapy; DNA-PK; PP2A; Rapamycin; mTOR

PMID:
23536185
PMCID:
PMC3650361
DOI:
10.1074/jbc.M113.463679
[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center