Fas‐Fas ligand signaling pathway mediates an interleukin‐12–induced rejection of a murine prostate tumor system

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Abstract
BACKGROUND: Recent data suggest that anti‐tumor activities of interleukin‐12 (IL‐12) involve the induction of apoptosis. Fas (APO‐1/CD95) is a type I membrane protein that is capable of initiating an apoptosis signaling pathway when bound to its ligand (FasL). We undertook this study to test the hypothesis that Fas‐FasL–mediated apoptosis plays a role in IL‐12–induced tumor regression.METHODS: An mIL‐12 expression vector driven by cytomegalovirus promoter was used to express murine IL‐12 cDNA in the RM‐9 murine prostate carcinoma cell line. Control RM‐9 cells and RM‐9 cells stably transfected with IL‐12 gene (RM‐9‐IL12) were inoculated subcutaneously in 4‐ to 6‐week‐old male C57BL/J6 mice. Tumor size was measured every 3 days. Western blot and immunohistochemical assays were used to evaluate Fas and FasL protein expression. In situ fluorescent end labeling was used to label apoptotic cells.RESULTS: IL‐12–expressing RM‐9 prostate carcinoma cells transplanted into C57BL/J6 mice grew more slowly than control RM‐9 cells and vector control RM‐9‐Luc cells. The average survival time of the RM‐9‐IL12 mice was longer than 53 days, whereas the mean survival for mice transplanted with control RM‐9 cells was only 16 days. Apoptotic cells were more numerous in RM‐9‐IL12 tumors: 10.3% vs. 1.5% in control (P = 0.001). Fas and FasL proteins were increased approximately twofold in the RM‐9‐IL12 tumors compared with the RM‐9 control tumors as determined by Western blot and immunohistochemical analyses (P < 0.05).CONCLUSION: The Fas‐FasL–mediated apoptosis pathway may contribute to the IL‐12–induced rejection of prostate carcinoma. Prostate 53: 69–76, 2002.

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