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[Cancer Research 63, 7365-7376, November 1, 2003]
© 2003 American Association for Cancer Research

Regular Articles

{alpha}-Methylacyl-CoA Racemase as an Androgen-Independent Growth Modifier in Prostate Cancer1

Shan Zha, Sacha Ferdinandusse, Simone Denis, Ronald J. Wanders, Charles M. Ewing, Jun Luo, Angelo M. De Marzo and William B. Isaacs2

Brady Urological Institute [S. Z., C. M. E., J. L., A. M. D. M., W. B. I.], Johns Hopkins Oncology Center [A. M. D. M., W. B. I.], and Department of Pathology [A. M. D. M.], Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, and Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands [S. F., S. D., R. J. W.]

{alpha}-Methylacyl-CoA racemase (AMACR) is an enzyme involved in ß-oxidation of branched-chain fatty acids and bile acid intermediates. Recent work has identified AMACR as a new diagnostic marker for prostate cancer (PCa). The data from the present study suggest that AMACR is also functionally important for the growth of PCa cells. Overexpressed AMACR from both clinical tissues and PCa cell lines is wild type by sequence analysis and functionally active by enzymatic assay. Correspondingly, enzyme activity of AMACR increases ~4-fold in PCa in comparison with adjacent normal prostate. Small interference RNA (siRNA) against AMACR, but not the control inverted siRNA, reduced the expression of AMACR and significantly impaired proliferation of the androgen-responsive PCa cell line LAPC-4. No effect was observed in HeLaS3 cells, which express AMACR at a low level. Cell cycle analyses revealed a G2-M cell cycle arrest in LAPC-4 cells treated with siRNA compared with mock treatment or control inverted siRNA. Expression of a siRNA-resistant form of AMACR in LAPC-4 cells protects the cells from growth arrest after AMACR-specific siRNA treatment. Data from Western blotting and luciferase-based reporter assays suggest that the function and expression of AMACR are independent of androgen receptor-mediated signaling. Moreover, simultaneous inhibition of both the AMACR pathway by siRNA and androgen signaling by means of androgen withdrawal or antiandrogen suppressed the growth of LAPC-4 cells to a greater extent than either treatment alone. Taken together, these data suggest that AMACR is essential for optimal growth of PCa cells in vitro and that this enzyme has the potential to be a complementary target with androgen ablation in PCa treatment.




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