title: IGF2 increases de novo steroidogenesis in prostate cancer cells.
abstract: IGF2 is a mitogenic foetal growth factor commonly over-expressed in cancers, including prostate cancer (PC). We recently demonstrated that insulin can activate de novo steroidogenesis in PC cells, a major pathway for reactivation of androgen pathways and PC progression. IGF2 can activate the IGF1 receptor (IGF1R) or insulin receptor (INSR) or hybrids of these two receptors. We therefore hypothesized that IGF2 may contribute to PC progression via de novo steroidogenesis. IGF2 mRNA but not IGF2 receptor mRNA expression was increased in patient samples during progression to castrate-resistant PC as was immunoreactivity to INSR and IGF1R antibodies. Treatment of androgen receptor (AR)-positive PC cell lines LNCaP and 22RV1 with IGF2 for 48 h resulted in increased expression of steroidogenic enzyme mRNA and protein, including steroid acute regulatory protein (StAR), cytochrome p450 family member (CYP)17A1, aldo-keto reductase family member (AKR)1C3 and hydroxysteroid dehydrogenase (HSD)17B3. IGF2 treatment resulted in increased steady state steroid levels and increased de novo steroidogenesis resulting in AR activation as demonstrated by PSA mRNA induction. Inhibition of the IGF1R/INSR signalling axis attenuated the effects of IGF2 on steroid hormone synthesis. We present a potential mechanism for prostatic IGF2 contributing to PC progression by inducing steroidogenesis and that IGF2 signalling and related pathways present attractive targets for PC therapy.
authors: Institute of Health and Biomedical Innovation, Australian Prostate Cancer Research Centre - Queensland, Princess Alexandra Hospital, Queensland University of Technology, Level 1, Building 1, 199 Ipswich Road, Brisbane, Queensland 4102, Australia.
authors: Amy A
authors: AA
authors: Lubik
authors: Jennifer H
authors: JH
authors: Gunter
authors: Brett G
authors: BG
authors: Hollier
authors: Susan
authors: S
authors: Ettinger
authors: Ladan
authors: L
authors: Fazli
authors: Nataly
authors: N
authors: Stylianou
authors: Stephen C
authors: SC
authors: Hendy
authors: Hans H
authors: HH
authors: Adomat
authors: Martin E
authors: ME
authors: Gleave
authors: Michael
authors: M
authors: Pollak
authors: Adrian
authors: A
authors: Herington
authors: Colleen C
authors: CC
authors: Nelson
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000235:genetics; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D013256:Steroids; D007335:Insulin-Like Growth Factor II; D017430:Prostate-Specific Antigen