Heat shock protein 27 increases after androgen ablation and plays a cytoprotective role in hormone-refractory prostate cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2004-09, Vol.64 (18), p.6595-6602
• Main Authors: ROCCHI, Palma, SO, Alan, KOJIMA, Satoko, SIGNAEVSKY, Maxim, BERALDI, Eliana, FAZLI, Ladan, HURTADO-COLL, Antonio, YAMANAKA, Kazuki, GLEAVE, Martin
• Format: Article
• Language: English
• Subjects: Androgens - deficiency; Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Biological and medical sciences; Cell Division - drug effects; Cell Division - genetics; Disease Progression; Dose-Response Relationship, Drug; Heat-Shock Proteins - antagonists & inhibitors; Heat-Shock Proteins - biosynthesis; Heat-Shock Proteins - genetics; Humans; Male; Medical sciences; Mice; Mice, Nude; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Oligonucleotides, Antisense - genetics; Oligonucleotides, Antisense - pharmacology; Paclitaxel - pharmacology; Pharmacology. Drug treatments; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; RNA, Small Interfering - genetics; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-03-3998

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.