Cotargeting stress-activated Hsp27 and autophagy as a combinatorial strategy to amplify endoplasmic reticular stress in prostate cancer.
Hsp27 is a stress-activated multifunctional chaperone that inhibits treatment-induced apoptosis and causes treatment resistance in prostate and other cancers. We previously showed that targeted suppression of Hsp27 sensitizes cancer cells to hormone and chemotherapy. However, mechanisms by which Hsp27 confers cell treatment resistance are incompletely defined. Here, we report that Hsp27 protects human prostate cancer cells against proteotoxic stress induced by proteasome inhibition, and that Hsp27 silencing using siRNA or antisense (OGX-427) induced both apoptosis and autophagy through mechanisms involving reduced proteasome activity and induction of endoplasmic reticulum (ER) stress. We found that autophagy activation protected against ER stress-induced cell death, whereas inhibition of autophagy activation following Hsp27 silencing using either pharmacologic inhibitors or atg3 silencing enhanced cell death. Importantly, cotargeting Hsp27 and autophagy by combining OGX-427 with the autophagy inhibitor, chloroquine, significantly delayed PC-3 prostate tumor growth in vivo. These findings identify autophagy as a cytoprotective, stress-induced adaptive pathway, activated following disruption of protein homeostasis and ER stress induced by Hsp27 silencing. Combinatorial cotargeting cytoprotective Hsp27 and autophagy illustrates potential benefits of blocking activation of adaptive pathways to improve treatment outcomes in cancer.
The Vancouver Prostate Centre and Department of Urological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Masafumi
M
Kumano
Junya
J
Furukawa
Masaki
M
Shiota
Anousheh
A
Zardan
Fan
F
Zhang
Eliana
E
Beraldi
Romina M
RM
Wiedmann
Ladan
L
Fazli
Amina
A
Zoubeidi
Martin E
ME
Gleave
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D015870:Gene Expression; D020868:Gene Silencing; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D055551:HSP27 Heat-Shock Proteins; D007976:Leupeptins; D016376:Oligonucleotides, Antisense; D025801:Ubiquitin; D002738:Chloroquine; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde