Cyclosporin A inhibits growth of autocrine tumour cell lines by destabilizing interleukin-3 mRNA

In T cells, cyclosporin A (CsA) exerts its immunosuppressive effect by preventing transcriptional induction of the expression of interleukin(IL)-2. This is achieved by a mechanism that involves binding of a CsA-cyclophilin complex to calcineurin, which in turn inhibits the phosphatase-controlled translocation of transcription factor NFAT to the nucleus. We have previously identified IL-3 as an autocrine oncogenic regulator in tumour cell lines generated by introducing the v-H-ras oncogene into IL-3-dependent mast cells. Here we report that CsA specifically blocks autocrine tumour cell growth. The mechanism involves down-regulation of IL-3 expression by destabilization of the messenger RNA and requires ongoing transcription. Transcripts from exogenous IL-3 genes lacking the (A+U)-rich element (ARE) in the 3' untranslated terminal repeat could not be destabilized, suggesting that at least part of this sequence, which is known to mediate decay of short-lived mRNA, participates in a CsA-sensitive regulatory mechanism.