Heat Shock Protein 27 Increases after Androgen Ablation and Plays a Cytoprotective Role in Hormone-Refractory Prostate Cancer

Abstract

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.

Regenerating islet‐derived family member, 4 modulates multiple receptor tyrosine kinases and mediators of drug resistance in cancer

“…43 Hsp27 has been reported to be elevated in many human tumors and is a predictor of poor clinical outcome (androgen-independence), as it has a cytoprotective role by interfering with many key regulators of apoptosis. 37,44 Multiple RTKs, Bcl-2 and Hsp27 have all been implicated in hormone resistance, 41,45,46 and we have shown that Reg IV modulates the spectrum, therefore suggesting that a Reg IVtargeted therapy could have utility in drug resistant patient populations. In addition to expanding our understanding of signaling downstream of Reg IV, our results support a potential therapeutic benefit in neutralizing Reg IV activity in Reg IV-positive patient populations.…”

“…35 In addition, the expression of IGF-1, which signals through IGF1R and IR, has been correlated with an elevated risk of developing prostate cancer, 36 and IGF-1 signaling has been implicated in resistance to both general cytotoxic treatment regimens and to targeted therapies. 37 While the mechanism by which Reg IV is impacting these RTKs is not clear, it is of note that RTKs physically interact with each other (e.g., EGFR and…”

Hsp27 knockdown using nucleotide-based therapies inhibit tumor growth and enhance chemotherapy in human bladder cancer cells

“…Electrophoresis, hybridization, and washing conditions were carried out as reported previously (18,23). Human Hsp27 cDNA probe was obtained from StressGen (Victoria, BC, Canada).…”

“…Antisense oligonucleotides (ASO) are powerful tools that specifically hybridize with complementary mRNA regions to form RNA/DNA duplexes to inhibit target gene expression in a sequencespecific manner. Several ASOs targeting genes involved in neoplastic progression have been evaluated as potential therapeutic agents (17,18). In fact, the combined use of ASO with other compounds, such as chemotherapeutic agents, has shown synergistic antineoplastic effects in several tumor models (18,19).…”

“…Several ASOs targeting genes involved in neoplastic progression have been evaluated as potential therapeutic agents (17,18). In fact, the combined use of ASO with other compounds, such as chemotherapeutic agents, has shown synergistic antineoplastic effects in several tumor models (18,19). OGX-427 (OncoGenex, Vancouver, BC, Canada) is a second-generation ASO, generated using the 2 ¶-O-(2-methoxy) ethyl (2 ¶-MOE) backbone, that targets Hsp27 mRNA.…”