Novel cross talk between MEK and S6K2 in FGF-2 induced proliferation of SCLC cells

Here, we show that fibroblast growth factor-2 (FGF-2) induces proliferation of H-510 and H-69 small cell lung cancer (SCLC) cells. However, the optima l response to FGF-2 was obtained at 10-fold lower concentrations in H-510 c ells. This correlated with the selective activation of the mitogen-activate d protein kinase kinase (MEK) pathway in H-510, but not H-69 cells. Moreove r, inhibition of MEK with PD098059 blocked FGF-2-induced proliferation in H -510 cells only. Similarly, ribosomal protein S6 kinase 2 (S6K2), a recentl y identified homologue of S6K1 was activated by FGF-2 in H-510, but not H-6 9 cells. This activation was independent of phosphatidylinositol-3 kinase, but was sensitive to inhibition of the MEK pathway. These data suggest that S6K2 is a novel downstream target of MEK. The potency of FGF-2 in H-510 ce lls might reflect this additional MEK/S6K2 signalling. In contrast to S6K2, S6K1 was activated in both SCLC cell lines. Inhibition of the mammalian ta rget of rapamycin with 10 ng/ml rapamycin blocked S6K1 activation and proli feration of both lines. However, even at 100 ng/ml, rapamycin only partiall y inhibited S6K2. Strikingly, this correlated with inhibition of MEK signal ling. Our data indicate that S6K1, and possibly S6K2, are involved in FGF-2 -induced SCLC cell growth, a notion supported by the overexpression and hig her baseline activity of both isoforms in SCLC lines, as compared to normal human type-II pneumocytes.