1289 A MECHANISM FOR ANDROGEN-INDEPENDENT PROSTATE CANCER THROUGH MODULATION OF ANDROGEN RECEPTOR SIGNALING BY THE P21-ACTIVATED KINASE 6 (PAK6)

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research VII1 Apr 20101289 A MECHANISM FOR ANDROGEN-INDEPENDENT PROSTATE CANCER THROUGH MODULATION OF ANDROGEN RECEPTOR SIGNALING BY THE P21-ACTIVATED KINASE 6 (PAK6) Min Zhang, Michael Siedow, Gregory Saia, and Arnab Chakravarti Min ZhangMin Zhang More articles by this author , Michael SiedowMichael Siedow More articles by this author , Gregory SaiaGregory Saia More articles by this author , and Arnab ChakravartiArnab Chakravarti More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.873AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES p21-activated kinase 6 (PAK6) is a serine/threonine kinase belonging to the p21-activated kinase (PAK) family. PAK6 was first identified in a yeast two-hybrid screen for novel androgen receptor (AR) interactors, but its functions have not been established. In this study, we explored the role of PAK6 in mediation hormone resistance in prostate cancer cells. METHODS PAK6 expression was detected in androgen deprived prostate cancer cell line LNCaP. Short hairpin RNA (shRNA) was used to attenuate PAK6 expression in LNCaP cells, and apoptosis and cell cycle distribution were assessed in these cells. Given that AR can be phosphorylated by either the AKT or the mitogen-activated protein kinase (MAPK) pathway and becomes a ligand-independent AR, we investigated the effect of PAK6 on the cross-talks between AR signaling and AKT/MAPK pathways. RESULTS We found that PAK6 expression in LNCaP PCa cells was markedly increased when the cells were cultured for 8 weeks in steroid hormone depleted medium. Antagonism of PAK6 using short hairpin RNA (shRNA) significantly increased antiangogen bicalutamide-induced apoptosis and G1 arrest. These finds implied that PAK6 may play a role in the development of androgen independent prostate cancer. Knockdown of PAK6 in LNCaP cells diminished AKT phosporylation at Ser473 and Thr308 as well as p44/42 MAPK phophorylation at Thr202 and Tyr204, indicating that overexpression of PAK6 during androgen deprivation may activate AR signaling by phosporylation of both AKT and MAPK. CONCLUSIONS These findings extended the current vision of PAK6 functions, and indicated that PAK6 may be involved in androgen-independent prostate cancer development through modulation of AR signaling. Columbus, OH© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e499 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Min Zhang More articles by this author Michael Siedow More articles by this author Gregory Saia More articles by this author Arnab Chakravarti More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...