EGF receptor (EGFR) is a receptor-type tyrosine kinase. Several lines of evidence indicate that EGF and TGFα, which are ligands of EGFR, are involved in hormone-refractory growth and poor prognosis of a subgroup of human prostate cancer. To elucidate the role of EGFR and its ligands in prostate cancer progression, we investigated the regulation of PSA, a surrogate marker for prostate cancer, by EGFR using LNCaP cells. EGF, TGFα and EGFR inhibitor (AG1478) were administered to the LNCaP cells under the androgen-depleted culture condition, mimicking androgen-ablation therapy. The protein levels of PSA, EGFR and androgen receptor (AR) were examined by western blot analyses. In addition, immunohistochemical staining of PSA, EGF and EGFR was carried out using the human prostatic cancer archival specimen. A 48-hr administration of 10 ng/ml EGF or 10 ng/ml TGFα stimulated the growth of LNCaP cells by approximately 1.5-fold, compared to that of control cells. Concurrently, PSA expression and secretion were suppressed by over 50%, lower than that of control cells. Furthermore, an EGFR inhibitor, AG1478, abrogated the PSA suppression effect by EGF or TGFα, concurred with the suppression of tyro-phosphorylation levels of EGFR. These results thus indicate that the suppression of PSA expression by EGF and TGFα was through the EGFR signaling pathway. Interestingly, in EGF-treated LNCaP cells, the AR level was also decreased. Additionally, the immunohistochemical staining of the prostatic cancer tissue revealed a significant inverse correlation between the cellular level of PSA and EGF as well as EGFR, consistent with the observations in LNCaP cells in culture. In prostate cancer, androgen-independent PSA secretion serves as a surrogate marker for hormone-refractory prostate cancer. Our results in this study clearly show that EGFR signaling pathway can negatively regulate androgen-independent PSA expression. This EGFR signaling may induce the alteration of AR expression, which results in PSA suppression.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]