title: Id-1 expression induces androgen-independent prostate cancer cell growth through activation of epidermal growth factor receptor (EGF-R).
abstract: The failure of prostate cancer treatment is largely due to the development of androgen independence, since the androgen depletion therapy remains the front-line option for this cancer. Previously, we reported that over-expression of the helix-loop-helix protein Id-1 was associated with progression of prostate cancer and ectopic expression of Id-1 induced serum-independent proliferation in prostate cancer cells. In the present study, we investigated if exogenous Id-1 expression in the androgen sensitive LNCaP cells had any effect on androgen-dependent cell growth and studied the molecular mechanisms involved. Using stable Id-1 transfectants, we found that expression of Id-1 was able to reduce androgen-stimulated growth and S phase fraction of the cell cycle in LNCaP cells, indicating that Id-1 may be involved in the development of androgen independence in these cells. The Id-1-induced androgen-independent prostate cancer cell growth was correlated with up-regulation of EGF-R (epidermal growth factor-receptor) and PSA (prostate specific antigen) expression, as confirmed by western blotting analysis and luciferase assays. In contrast, down-regulation of Id-1 in androgen-independent DU145 cells by its antisense oligonucleotides resulted in suppression of EGF-R expression at both transcriptional and protein levels. In addition, the results from immunohistochemistry study showed that Id-1 expression was significantly elevated in hormone refractory prostate cancer tissues when compared with the hormone-dependent tumours. Our results suggest that up-regulation of Id-1 in prostate cancer cells may be one of the mechanisms responsible for developing androgen independence and this process may be regulated through induction of EGF-R expression. Inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of androgen-independent prostate cancer cell growth.
authors.affiliation: Cancer Biology Group, Department of Anatomy, Central Laboratory of Institute of Molecular Technology for Drug Discovery and Synthesis, University of Hong Kong, 21 Sassoon Road, Hong Kong, SAR, China.
authors.forename: Ming-Tat
authors.initials: MT
authors.lastname: Ling
authors.forename: Xianghong
authors.initials: X
authors.lastname: Wang
authors.forename: Davy T
authors.initials: DT
authors.lastname: Lee
authors.forename: P C
authors.initials: PC
authors.lastname: Tam
authors.forename: Sai-Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Yong-Chuan
authors.initials: YC
authors.lastname: Wong
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D051798:Inhibitor of Differentiation Protein 1; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000473:pathology*; D012097:Repressor Proteins; D013450:Sulfones / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection; D014183:Transplantation, Heterologous
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000728:Androgens; C497453:ID1 protein, human; C497455:Idb1 protein, mouse; D051798:Inhibitor of Differentiation Protein 1; D016328:NF-kappa B; D009570:Nitriles; D012097:Repressor Proteins; D013450:Sulfones; D014157:Transcription Factors; D066246:ErbB Receptors