FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2 |
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Authors: | Pardo Olivier E Wellbrock Claudia Khanzada Umme K Aubert Muriel Arozarena Imanol Davidson Sally Bowen Frances Parker Peter J Filonenko V V Gout Ivan T Sebire Neil Marais Richard Downward Julian Seckl Michael J |
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Affiliation: | Lung Cancer Biology Group, Cancer Research UK, Imperial College London, Hammersmith Hospitals Campus, Du Cane Road, London, UK. |
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Abstract: | Patients with small cell lung cancer (SCLC) die because of chemoresistance. Fibroblast growth factor-2 (FGF-2) increases the expression of antiapoptotic proteins, XIAP and Bcl-X(L), and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multiprotein complex comprising B-Raf, PKCepsilon and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKCepsilon or S6K2 abolishes FGF-2-mediated survival. In contrast, overexpression of PKCepsilon increases XIAP and Bcl-X(L) levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-X(L) and prosurvival effects. However, increased S6K1 kinase activity has no such effect. Thus, S6K2 but not S6K1 mediates prosurvival/chemoresistance signalling. |
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