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.

Reassessment of Id1 Protein Expression in Human Mammary, Prostate, and Bladder Cancers Using a Monospecific Rabbit Monoclonal Anti-Id1 Antibody

“…Mobilization of endothelial cell progenitors from the bone marrow is also severely perturbed in Id knockout mice consistent with this hypothesis (10,11). On the other hand, a role for Id1 in modulating tumor epithelial cell behavior is suggested by the fact that overexpression of Id1 in cell lines results in increased invasiveness and metastatic potential of these cells, whereas reduction of high levels of Id1 present endogenously in these lines leads to an inhibition of these properties (12)(13)(14)(15)(16)(17).…”

A Specific Screening Strategy to Reduce Prostate Cancer Mortality

“…Reporter expression of the diagnostic system was driven by the cancer-specific expression of Id1, which is a documented indicator of tumor malignancy with no expression found in BPH and normal prostate tissue [11][12][13][14][15][24][25][26][27][28]. The present study used a panel of prostate cancer cells with The dependency of the diagnostic vector on adequate expression of Id1 represents a limitation of the current system for detecting less aggressive cancers.…”

“…Id1 gene expression is cancer-specific and has been demonstrated to have increasing levels in human tumors that correlate with increasing Gleason grade and progression [10]. Several studies [11][12][13][14][15] have shown expression of Id1 to be an indicator of malignancy with no expression found in cases of benign prostate hyperplasia (BPH) and normal prostate tissue. The correlation between increased Id1 expression and cancer aggressiveness supports the use of the Id1 promoter for controlling diagnostic reporter function.…”

Prostate Cancer: The Id1 Story

“…We therefore investigated the EGFR expression in Id1 transfected clones. The results showed that EGFR expression was increased significantly indicating that Id1 transfection resulted in increased expression of EGFR [17]. Treatment of DU145 cells with antisense Id1 resulted in downregulation of EGFR indicating the relationship of Id1 and expression of EGFR [17].…”