Docetaxel down‐regulates the expression of androgen receptor and prostate‐specific antigen but not prostate‐specific membrane antigen in prostate cancer cell lines: Implications for PSA surrogacy

Abstract

Docetaxel (DOC) has potent anti-tumor efficacy as a result of promoting microtubule assembly and microtubule bundling thereby impairing mitosis. Knowing that some anti-microtubule agents affect the polarity of prostate-specific membrane antigen (PSMA) expression and that androgen ablation can up-regulate PSMA expression, we sought to determine any effect of DOC on PSMA expression in prostate cancer (PC) cell lines as a prelude to a clinical effort. As controls, we also looked at the expression of androgen receptor (AR) and prostate-specific antigen (PSA). The effect of DOC on cell viability and PSMA, AR, and PSA expression was examined by flow cytometry and immunoblotting using LNCaP, CWR22Rv1, and MDA-PCa-2b cells. The effect of DOC on PSA levels of LNCaP and MDA-PCa-2b cells was also measured in conditioned media. The effect of DOC was also studied using LNCaP and MDA-PCa-2b cells that were transfected to over-express AR. PSMA levels were not affected by DOC treatment. Unexpectedly, we found DOC significantly down-regulated both AR and PSA in a dose-dependent manner in the cell lines studied. Over-expression of AR partially abrogated the cytotoxic effects of DOC. While DOC did not affect PSMA expression, it was unexpectedly found to down-regulate AR and PSA. DOC-induced down-regulation of AR might be one of the anti-tumor mechanisms active in PC. Down-regulation of PSA may account for the significantly higher PSA response rates (45-50%) relative to measurable response rates (8-17%) reported in DOC PC trials and have implications for PSA surrogacy observations derived from DOC trials.