Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer.
Heat shock protein 27 (Hsp27) is a chaperone implicated as an independent predictor of clinical outcome in prostate cancer. Our aim was to characterize changes in Hsp27 after androgen withdrawal and during androgen-independent progression in prostate xenografts and human prostate cancer to assess the functional significance of these changes using antisense inhibition of Hsp27. A tissue microarray was used to measure changes in Hsp27 protein expression in 232 specimens from hormone naive and posthormone-treated cancers. Hsp27 expression was low or absent in untreated human prostate cancers but increased beginning 4 weeks after androgen-ablation to become uniformly highly expressed in androgen-independent tumors. Androgen-independent human prostate cancer PC-3 cells express higher levels of Hsp27 mRNA in vitro and in vivo, compared with androgen-sensitive LNCaP cells. Phosphorothioate Hsp27 antisense oligonucleotides (ASOs) and small interference RNA potently inhibit Hsp27 expression, with increased caspase-3 cleavage and PC3 cell apoptosis and 87% decreased PC3 cell growth. Hsp27 ASO and small interference RNA also enhanced paclitaxel chemosensitivity in vitro, whereas in vivo, systemic administration of Hsp27 ASO in athymic mice decreased PC-3 tumor progression and also significantly enhanced paclitaxel chemosensitivity. These findings suggest that increased levels of Hsp27 after androgen withdrawal provide a cytoprotective role during development of androgen independence and that ASO-induced silencing can enhance apoptosis and delay tumor progression.
Rocchi
Palma
P
The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, and Division of Urology, University of British Columbia, Vancouver, British Columbia, Canada.
So
Alan
A
Kojima
Satoko
S
Signaevsky
Maxim
M
Beraldi
Eliana
E
Fazli
Ladan
L
Hurtado-Coll
Antonio
A
Yamanaka
Kazuki
K
Gleave
Martin
M
D000728:Androgens / Q000172:deficiency*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics
D000728:Androgens; D000972:Antineoplastic Agents, Phytogenic; D006360:Heat-Shock Proteins; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D017239:Paclitaxel