PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt

doi:10.1073/pnas.0400921101

PIKE-A is amplified in human cancers and prevents apoptosis by up-regulating Akt

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322

Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD (received for review February 9, 2004)

Abstract

PIKE-A (PIKE-activating Akt), an isoform of PIKE GTPase that enhances phosphatidylinositol 3-kinase (PI3-kinase) activity, specifically binds to active Akt but not PI3-kinase. PIKE-A stimulates Akt activity in a GTP-dependent manner and promotes invasiveness of cancer cell lines. Here, we show that PIKE-A is amplified in a variety of human cancers and that amplified PIKE-A directly stimulates Akt and inhibits apoptosis compared to cells with normal PIKE-A copy number. Overexpression of PIKE-A wild-type but not dominant-negative mutant stimulates Akt activity and prevents apoptosis. Moreover, knockdown of PIKE-A diminishes Akt activity and increases apoptosis. Our findings suggest that PIKE-A amplification contributes to cancer cell survival and progression by inhibiting apoptosis through up-regulating Akt.

Footnotes

↵ * To whom correspondence should be addressed. E-mail: kye{at}emory.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: PI3-K, phosphatidylinositol 3-kinase; DAPI, 4,6-diamidino-2-phenylindole; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide.