Id-1 expression induces androgen-independent prostate cancer cell growth through activation of epidermal growth factor receptor (EGF-R).
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.
Ling
Ming-Tat
MT
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.
Wang
Xianghong
X
Lee
Davy T
DT
Tam
P C
PC
Tsao
Sai-Wah
SW
Wong
Yong-Chuan
YC
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
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