Castration-induced increases in insulin-like growth factor-binding protein 2 promotes proliferation of androgen-independent human prostate LNCaP tumors.
Activation of alternative growth factor pathways after androgen withdrawal is one mechanism mediating androgen-independent (AI) progression in advanced prostate cancer. Insulin-like growth factor (IGF) I activation is modulated by a family of IGF binding proteins (IGFBPs). Although IGFBP-2 is one of the most commonly overexpressed genes in hormone refractory prostate cancer, the functional significance of changes in IGF-I signaling during AI progression remains poorly defined. In this article, we characterize changes in IGFBP-2 in the LNCaP tumor model after androgen withdrawal and evaluate its functional significance in AI progression using gain-of-function and loss-of-function analyses. IGFBP-2 mRNA and protein levels increase 2-3-fold after androgen withdrawal in LNCaP cells in vitro in LNCaP tumors during AI progression in vivo. Increased IGFBP-2 levels after castration were also identified using a human prostate tissue microarray of untreated and posthormone therapy-treated prostatectomy specimens. LNCaP cell transfectants that stably overexpressed IGFBP-2 progressed more rapidly after castration than control tumors. Antisense oligonucleotides (ASOs) targeting the translation initiation site of IGFBP-2 reduced IGFBP-2 mRNA and protein expression by >70% in a dose-dependent and sequence-specific manner. ASO-induced decreases in IGFBP-2-reduced LNCaP cell growth rates and increased apoptosis 3-fold. LNCaP tumor growth and serum prostate-specific antigen levels in mice treated with castration plus adjuvant IGFBP-2 ASOs were significantly reduced compared with mismatch control oligonucleotides. Increased IGFBP-2 levels after androgen ablation may represent an adaptive response that helps potentiate IGF-I-mediated survival and mitogenesis and promote androgen-independent tumor growth. Inhibiting IGFBP-2 expression using ASO technology may offer a treatment strategy to delay AI progression.
Kiyama
Satoshi
S
The Prostate Centre, Vancouver General Hospital, and Division of Urology, University of British Columbia, Canada.
Morrison
Kevin
K
Zellweger
Tobias
T
Akbari
Majid
M
Cox
Michael
M
Yu
Duan
D
Miyake
Hideaki
H
Gleave
Martin E
ME
D000728:Androgens / Q000502:physiology*; D001483:Base Sequence; D002455:Cell Division; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D014176:Protein Biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects
D000728:Androgens; D017931:DNA Primers; D018971:Insulin-Like Growth Factor Binding Protein 2; D020319:Oligodeoxyribonucleotides, Antisense