Sensitization of immunoresistant prostate carcinoma cell lines to Fas/Fas ligand-mediated killing by cytotoxic lymphocytes: Independence of de novo protein synthesis
✍ Scribed by Frost, Patrick J.; Belldegrun, Arie; Bonavida, Benjamin
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 350 KB
- Volume
- 41
- Category
- Article
- ISSN
- 0270-4137
No coin nor oath required. For personal study only.
✦ Synopsis
We recently reported that drug-resistant prostate tumor cells (DU145, PC-3) are resistant to Fas-mediated killing by cytotoxic lymphocytes, and that this resistance can be overcome by treatment with subtoxic concentrations of chemotherapeutic drugs. Fas belongs to the tumor necrosis factor (TNF) family of receptors. Since resistance to TNF-␣mediated killing has been shown to be due, in part, to the presence of protective factors and that inhibitors of protein synthesis can sensitize cells to TNF-␣ killing, we hypothesized that resistance to Fas-mediated killing may be due to similar mechanisms. Since sensitization is achieved with chemotherapeutic drugs, and some chemotherapeutic drugs can also inhibit protein synthesis, we tested whether sensitization of prostate tumor cells to Fas ligand (Fas-L) occurred through inhibition of protein synthesis in a manner analogous to that of TNF-␣. METHODS. The effect of chemotherapeutic drugs on protein synthesis in DU145 and PC-3 cells was characterized by 3 H-leucine incorporation assays. We also determined the ability of inhibitors of protein synthesis and chemotherapeutic drugs to sensitize Fas and TNF-resistant DU145 cells to killing. The ability of RNA (actinomycin-D, Act-D) and protein synthesis inhibitors (cyclohexamide (CHX), emetine) to block drug-mediated sensitization to Fas-L killing was analyzed. Sensitivity to Fas-L killing was determined by the 51 Cr-release assay using human lymphokine-activated killer cells (LAK) and tumor-infiltrating lymphocyte (TIL) effector cells and the murine Fas-L-expressing PMMI cells. RESULTS. The drugs cis-diamminedichloroplatinum (II) (CDDP), adriamycin (ADR), and etoposide (VP-16) sensitized DU145 and PC-3 cells to Fas killing. CDDP and ADR, which sensitized DU145 and PC-3 cells to Fas-L-and TNF-mediated killing, inhibited de novo