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Title: The role of JAKs and STATs in chemoresistance
Author: Carmo, Catarina Ramos do
ISNI:       0000 0004 2688 641X
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2010
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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.
Supervisor: Seckl, Michael Sponsor: Cancer Treatment and Research Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral