Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 277, Issue 34, Pages 30935-30941Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M201919200
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Funding
- NCI NIH HHS [R01 CA070297-06A1, R01 CA070297-10, CA 70297, R01 CA070297-09, R01 CA070297-12, R01 CA070297-08, R01 CA087767-04, R01 CA070297-07, R01 CA087767, R01 CA087767-01A2, R01 CA087767-05, R01 CA087767-02, R01 CA087767-03, R01 CA070297, CA 87767, R01 CA070297-11A2] Funding Source: Medline
- NIDDK NIH HHS [R01 DK061002] Funding Source: Medline
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PI3K/Akt plays a critical role in prostate cancer cell growth and survival. Recent studies have shown that the effect of PI3K/Akt in prostate cells is mediated through androgen signaling. The PI3K inhibitor, LY294002, and a tumor suppressor, PTEN, negatively regulate the PI3K/Akt pathway and repress AR activity. However, the molecular mechanisms whereby PI3K/Akt and PTEN regulate the androgen pathway are currently unclear. Here, we demonstrate that blocking the PI3K/Akt pathway reduces the expression of an endogenous AR target gene. Moreover, we show that the repression of AR activity by LY294002 is mediated through phosphorylation and inactivation of GSK3beta, a downstream substrate of PI3K/Akt, which results in the nuclear accumulation of beta-catenin. Given the recent evidence that beta-catenin acts as a coactivator of AR, our findings suggest a novel mechanism by which PI3K/Akt modulates androgen signaling. In a PTEN-null prostate cancer cell line, we show that PTEN expression reduces beta-catenin-mediated augmentation of AR transactivation. Using the mutants of beta-catenin, we further demonstrate that the repressive effect of PTEN is mediated by a GSK3beta-regulated degradation of beta-catenin. Our results delineate a novel link among the PI3K, wnt, and androgen pathways and provide fresh insights into the mechanisms of prostate tumor development and progression.
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