Knockdown of p21-activated Kinase 6 Inhibits Prostate Cancer Growth and Enhances Chemosensitivity to Docetaxel

OBJECTIVES To investigate whether silencing of p21-activated kinase 6 (PAK6) would inhibit prostate cancer growth and to assess the effect of PAK6 silencing when used in combination with docetaxel. PAK6 is a serine/threonine kinase belonging to the PAK family and has been implicated in cell motility, apoptosis, and transformation. METHODS Expression of PAK6 in PC-3, DU145, and LAPC4 prostate cancer cell lines was knocked down by small, interfering RNA (siRNA). Cellular proliferation, cell cycle distribution, the ability to undergo apoptosis, and the invasive capacity through matrigel were evaluated. Furthermore, in vivo growth of prostate cancer in nude mice treated with PAK6-siRNA alone or in combination with docetaxel was examined. RESULTS PAK6 was overexpressed in prostate cancer tissues. PAK6-siRNA efficiently and specifically downregulated the expression of PAK6 and inhibited cell growth of prostate cancer. It also suppressed invasive ability in matrigel and caused cell cycle arrest at the G(2)/M phase. Xenograft tumor growth in nude mice was inhibited significantly by PAK6-siRNA. The average weight of the harvested tumor was 46 +/- 8.5 mg in the PAK6-siRNA group, lower than the 451 +/- 22.3 mg in the control group (P <.05). Combined use of PAK6-siRNA and docetaxel produced a greater effect than docetaxel alone in both in vitro and in vivo models. CONCLUSIONS Knockdown of PAK6 expression produced an inhibitory effect on prostate cancer growth and enhanced chemosensitivity of docetaxel. PAK6 could be a valuable molecular target for the treatment of prostate cancer. UROLOGY 73: 1407-1411, 2009. (C) 2009 Elsevier Inc.