Conditional Akt activation promotes androgen-independent progression of prostate cancer

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Abstract

Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers.

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