P21-activated kinase 6 (PAK6) inhibits prostate cancer growth via phosphorylation of androgen receptor and tumorigenic E3 ligase murine double minute-2 (Mdm2).

The androgen receptor (AR) signaling pathway plays a crucial role in the development and growth of prostate malignancies. Regulation of AR homeostasis in prostate tumorigenesis has not yet been fully characterized. In the present study, we demonstrate that p21-activated kinase 6 (PAK6) inhibits prostate tumorigenesis by regulating AR homeostasis. First, ...
we demonstrated that in normal prostate epithelium, AR co-localizes with PAK6 in cytoplasm and translocates into nucleus in malignant prostate. Furthermore, AR phosphorylation at Ser578 by PAK6 promotes AR-E3 ligase murine double minute-2 (Mdm2) association, causing AR degradation upon subsequent androgen stimuli. We also showed that PAK6 phosphorylates Mdm2 on Thr158 and Ser186, which is critical for AR ubiquitin-mediated degradation. Moreover, we found that Thr158 collaborates with Ser186 for AR-Mdm2 association and AR ubiquitin-mediated degradation as it facilitates PAK6-mediated AR homeostasis. PAK6 knockdown promotes prostate tumor growth in vivo. Strikingly, we found a strong inverse correlation between PAK6 and AR expression in cytoplasm of prostate cancer cells. These observations indicate that PAK6 may be important for the maintenance of androgen-induced AR signaling homeostasis and in prostate malignancy, as well as being a possible new therapeutic target for AR-positive and hormone-sensitive prostate cancer.
J. Biol. Chem.
Date: Nov. 06, 2012
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