Activation of SAPK/JNK by camptothecin sensitizes androgen-independent prostate cancer cells to Fas-induced apoptosis

We have previously shown that the androgen-independent prostate cancer cell s DU145, despite expressing Fas and Fast, were resistant to anti-fas-induce d apoptosis, and that this resistance could be overcome by pretreating the cells with sublethal doses of camptothecin. Here, we provide evidence that SAPK/JNK activity is required for camptothecin sensitization to anti-fas-in duced apoptosis. Camptothecin, but not Fas ligation, was shown to activate SAPK/JNK in a time-dependent manner, and to induce c-Jun expression. The ef fects were more prominent in cells treated with both camptothecin and anti- fas. The expression levels of MKP-1, a phosphatase which regulates SAPK/JNK and which has been implicated in prostate cancer resistance to apoptosis, remained unchanged, inhibition of caspases had no effect on the SAPK/JNK ac tivation, suggesting that this activation is an upstream event in the Fas-s ignalling pathway, and is independent of caspase activity. Antisense oligon ucleotides targeted to JNK1 and JNK2 reversed the effect of camptothecin. T hese results suggest that stress kinase activation can significantly influe nce the fate of androgen-independent prostate cancer cells following Fas re ceptor ligation. (C) 2000 Cancer Research Campaign.