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Fas-mediated Apoptosis in Human Prostatic Carcinoma Cell Lines¹

Departments of Pathology [O. W. R., T. J. W., R. A. G., M. B. C.], Microbiology [G. A. B., B. S. H.], and Urology [M. B. C.], University of Iowa, Iowa City, Iowa 52242; the Institute of Experimental Pathology, Oncology and Radiobiology, Kiev, Ukraine, 252022 [S. P. S.]; and LXR Biotechnology, Inc., Richmond, California 94804 [N. P., M. C. K. S. R. U.]

Of six prostatic carcinoma cell lines examined (ALVA31, DU145, JCA1, LNCaP, ND1, and PC3) by flow cytometric analysis, all were found to be positive for Fas antigen. Furthermore, of the prostate tissue specimens studied (six cases), all revealed Fas expression in benign and malignant epithelial cells. The agonistic anti-Fas monoclonal antibody (IPO-4) induced apoptosis in only two of six cell lines investigated, PC3 and ALVA31. PCR analysis indicated that all cell lines expressed normal transmembrane and death domains of Fas antigen. Using Western blot analysis, we found abundant expression of p53 in the cytoplasm of two Fas-resistant cell lines, DU145 and ND1, and did not find p53 in two Fas-sensitive cell lines, PC3 and ALVA31. Western blot and PCR analysis did not show consistent differences between cell lines examined in the expression of Bcl-2, Bcl-X_L, Bcl-X_S, and Bak. In contrast, Bax protein was not detected in two Fas-resistant cell lines, DU145 and ND1. We also showed that three Fas-resistant cell lines, DU145, ND1, and JCA1, expressed CD40, whereas the two Fas-sensitive cell lines, PC3 and ALVA31, were CD40 negative. Fas-sensitive cell lines were transfected with the cDNA encoding CD40, and the CD40-positive transfectant became more resistant to growth inhibition mediated by treatment with TNF- and anti-Fas monoclonal antibody. Treatment with cycloheximide converted the phenotype of resistant cell lines from Fas resistant to Fas sensitive. Moreover, anti-Fas treatment of both resistant and sensitive cell lines induced rapid tyrosine phosphorylation or dephosphorylation of multiple proteins. These results suggest that the apoptotic machinery involved in DNA fragmentation is already in place in Fas-resistant cell lines, and thus, Fas-mediated apoptosis could be a target for therapeutic intervention.

¹ Supported by Grant NAG9-824 from NASA (to M. B. C.), NIH Grants AI28847 and DK25295 (to G. A. B.), NIH postdoctoral training Grant T32AI07260 (to B. S. H.), and NIH Grant R29AI31265 (to T. J. W.). S. P. S. is a Howard Hughes Medical Institute International Research Scholar.

² To whom requests for reprints should be addressed, at Department of Pathology, 118 ML, University of Iowa Hospital and Clinics, Iowa City, IA 52242. Phone: (319) 335-8214; Fax: (319) 335-8348.

Received 11/ 5/96. Accepted 3/ 1/97.

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