IFN-gamma sensitization of prostate cancer cells to Fas-mediated death: a gene therapy approach.
While human prostate cancers and cell lines express Fas, most of these cell lines are resistant to Fas-mediated death. In the present studies we addressed the ability of IFN-gamma to influence Fas-mediated cell death in prostate cancer cells. In vitro exposure of the human cell lines LNCaP and PC3 and the mouse cell line RM-1 to agonist anti-Fas antibody and/or soluble Fas ligand resulted in killing of only PC3 cells. However, preincubation with IFN-gamma resulted in synergistic killing in all three cell lines. In vitro treatment of RM-1 with a replication-incompetent adenovirus expressing mouse FasL (Ad.FasL) resulted in maximal cell kill near 40%, which correlated with baseline Fas expression. The addition of IFN-gamma enhanced cell kill to a degree consistent with the resulting higher levels of Fas and maintained synergistic killing at very low doses of vector. Co-inoculation of orthotopic RM-1 primary tumors with Ad.mFasL and an adenovirus expressing mouse IL-12 (Ad.mIL-12) to drive host production of IFN-gamma negated the survival advantage of Ad.mIL-12 alone. However, the staggered injection of Ad.mIL-12 and Ad.FasL achieved almost threefold higher levels of apoptosis in primary tumor tissue and doubled median survival. Therefore, IFN-gamma is capable of bestowing increased sensitivity to Fas-mediated cell death in prostate cancer cells and, in a gene therapy approach, may define a powerful tool to treat prostate cancers.
Selleck
William A
WA
Department of Urology, Mount Sinai School of Medicine, One Gustave Levy L. Place, New York, NY 10029, USA.
Canfield
Steven E
SE
Hassen
Waleed A
WA
Meseck
Marcia
M
Kuzmin
Alexei I
AI
Eisensmith
Randy C
RC
Chen
Shu-Hsia
SH
Hall
Simon J
SJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D053222:Fas Ligand Protein; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D007371:Interferon-gamma / Q000235:genetics / Q000627:therapeutic use*; D018664:Interleukin-12 / Q000235:genetics / Q000627:therapeutic use; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000628:therapy*; D013997:Time Factors; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D018664:Interleukin-12; D007371:Interferon-gamma