Id-1 expression induces androgen independent prostate cancer cell growth through activation of epithelial growth factor receptor (EGF-R)

Abstract

The failure of prostate cancer treatment is largely due to the development of androgen independence, since androgen depletion therapy remains the front-line option for this cancer. Previously, we reported that over-expression of the helix-loop-helix (HLH) 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 whether 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 upregulation of EGF-R (epithelial 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. Our results suggest that upregulation 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 and PSA expression. Inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of androgen independent prostate cancer cell growth. [This work was supported by RGC grants to YCW (HKU7186/99M, HKU7314/01M and HKU7490/03M) and Area of Excellence Scheme (Project No. AoE/P-10/01)].