The role of JAKs and STATs in chemoresistance

Janus kinases (JAKs) and Signal Transducer and Activators of Transcription (STATs) are essential for signalling in response to the Interferons (IFNs) and most cytokines. Aberrant activation of JAKs and/or STATs has been observed in many human cancer cells, and several recent studies have suggested that STAT3 oncogenic pathways are also associated with intrinsic drug resistance. Chemoresistance is a major cause of failure of cancer treatment. In lung cancer cells chemoresistance can be mediated by Fibroblast Growth Factor 2 (FGF-2). In small cell lung cancer (SCLC) cell lines FGF-2 induces the expression of anti-apoptotic proteins via a MEK-ERK-dependent mechanism, which involves the formation of a multi-protein complex constituted by B-RAF, PKCε and S6K2. We investigated the generality of this phenomenon by analysing additional types of cells. Since there have been reports suggesting that activation of JAKs and/or STATs can occur downstream of FGF-2 we hypothesised that JAKs and/or STATs may also play a role in FGF-2 mediated chemoresistance pathway(s). In U2OS osteosarcoma cells, FGF-2 offers protection against cisplatin-induced cell death. As with SCLC cells this involves B-RAF, PKCε, S6K2, MAPKs and, most notably, JAKs (JAK1, JAK2, or TYK2), but not the STATs. Whereas the non-small lung cancer cells (NSCLC) HCC95 respond to FGF-2, HCC78 do not. In neither case, however, did FGF-2 mediate chemoresistance against cisplatin. Using RNA interference (RNAi), we have observed that ERK2 knockdown caused a concomitant reduction of STAT3 levels. The data suggest that ERK2, but not ERK1, levels can regulate STAT3 expression, and that ERK1 and ERK2 have non-overlapping functions. It also indicates that ERK2 protein levels can regulate STAT3, an important signal transducer and activator of transcription. The identification of a novel inter-play between the JAKs and MAPKs in the context of chemoresistance opens new avenues for treatment, which urgently warrant additional studies.EThOS - Electronic Theses Online ServiceCancer Treatment and Research TrustGBUnited Kingdo