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.