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.
BACKGROUND
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).


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Kuroda
Kenji
K
Laboratory of Urological Oncology, Department of Urology, Weill Cornell Medical College, New York, New York 10065, USA. kksmy@sa2.so-net.ne.jp
Liu
He
H
Kim
Sae
S
Guo
Ming
M
Navarro
Vincent
V
Bander
Neil H
NH
D000954:Antigens, Surface / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D006801:Humans; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D043823:Taxoids / Q000494:pharmacology*; D014162:Transfection
D000954:Antigens, Surface; D000970:Antineoplastic Agents; D011944:Receptors, Androgen; D043823:Taxoids; D000077143:Docetaxel; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen