615 HSP27 INHIBITION ACTIVATES THE UNFOLD PROTEIN RESPONSE AND AUTOPHAGY PATHWAY THROUGH INHIBITION OF PROTEASOME ACTIVITY IN PROSTATE CANCER (2011)

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011615 HSP27 INHIBITION ACTIVATES THE UNFOLD PROTEIN RESPONSE AND AUTOPHAGY PATHWAY THROUGH INHIBITION OF PROTEASOME ACTIVITY IN PROSTATE CANCER Masafumi Kumano, Junya Furukawa, Amina Zoubeidi, Shiota Masaki, Eliana Beraldi, and Martin Gleave Masafumi KumanoMasafumi Kumano Vancouver, Canada More articles by this author , Junya FurukawaJunya Furukawa Kobe, Japan More articles by this author , Amina ZoubeidiAmina Zoubeidi Vancouver, Canada More articles by this author , Shiota MasakiShiota Masaki Vancouver, Canada More articles by this author , Eliana BeraldiEliana Beraldi Vancouver, Canada More articles by this author , and Martin GleaveMartin Gleave Vancouver, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1468AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Hsp27 is induced by accumulation of unfolded protein aggregates following various stress conditions, and promotes folding of proteins to their native state or degrading misfolded proteins via the ubiquitin-proteasome pathway (UPP). The specific signaling that occurs between the endoplasmic reticulum (ER) and the nucleus in response to ER stress is known as the unfolded protein response (UPR). During the UPR, accumulated unfolded protein is either correctly refolded or degraded by the UPP. Recently, there has been an increased general interest in understanding the interactions of ER stress, UPP and autophagy pathway in protein clearance. However, it is still unclear whether ER stress-mediated autophagy by proteasome inhibition is involved in cell survival or cell death. Therefore, we hypothesize that inhibition of Hsp27 will enhance ER stress and treatment-induced cancer cell death by increasing unfolded protein burden. We set out to characterize the role of Hsp27 in ER stress and UPP in prostate cancer. METHODS Effects of Hsp27 silencing using siRNA or antisense inhibitor (OGX-427) or proteasome inhibition (MG132) on PC3 cell apoptosis and putative targets of UPR were compared. Proteasome activity was measured using fluorescent substrate of proteasome in Hsp27 inhibited or overexpressed PC3 cells. We also evaluated autophagy activity after Hsp27 knockdown and cell viability after combination treatment with Hsp27 knockdown +/− inhibition of autophagy by 3-methyladenine (3-MA). RESULTS Hsp27 expression and other components of the UPR were activated in PC-3 cells after treatment with MG132 with accumulation of ubiquitinated proteins. Hsp27 knockdown was associated with decreased proteasome activity, increased ubiquitinated protein levels, and activation of UPR, similar to that seen with MG132. In contrast, Hsp27 overexpressing PC3 cells exhibited increased proteasome activity and resistance to MG-132 induced cell death and UPR activation compared to control cells. The inhibition of Hsp27 also led to increased autophagy activity. Furthermore, the combination treatment with Hsp27 silencing and 3MA significantly reduced PC3 cell viability and induced apoptosis. CONCLUSIONS These results suggest that Hsp27 enhances the catalytic activity of the proteasome and increases the degradation rate of ubiquitinated proteins. Moreover, the inhibition of both Hsp27 and autophagy enhances prostate cancer cell death and represents a useful therapeutic strategy to target for anti-cancer therapies. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e247-e248 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masafumi Kumano Vancouver, Canada More articles by this author Junya Furukawa Kobe, Japan More articles by this author Amina Zoubeidi Vancouver, Canada More articles by this author Shiota Masaki Vancouver, Canada More articles by this author Eliana Beraldi Vancouver, Canada More articles by this author Martin Gleave Vancouver, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...