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| Subject Categories: Signal Transduction | Molecular Biology of Disease |
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| The EMBO Journal
(2006) 25, 3078–3088, doi:10.1038/sj.emboj.7601198 Published online 29 June 2006 |
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FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKC , B-Raf and S6K2 |
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| Olivier E Pardo1, 2, Claudia Wellbrock3, Umme K Khanzada1, Muriel Aubert1, Imanol Arozarena1, Sally Davidson1, Frances Bowen1, Peter J Parker4, V V Filonenko5, Ivan T Gout5, Neil Sebire1, Richard Marais3, Julian Downward2 and Michael J Seckl1 |
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1 Lung Cancer Biology Group, Cancer Research UK, Imperial College London, Hammersmith Hospitals Campus, Du Cane Road, London, UK 2 Signal Transduction, Cancer Research UK London Research Institute, London, UK 3 Signal Transduction Team, Cancer Research UK Centre of Cell and Molecular Biology, The Institute of Cancer Research, London, UK 4 Protein Phosphorylation Laboratories, Cancer Research UK London Research Institute, London, UK 5 Department of Biochemistry and Molecular Biology, University College London, London, UK To whom correspondence should be addressed Julian Downward, Signal Transduction, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK. Tel.: +44 20 7269 3533; Fax: +44 20 7269 3094; E-mail: julian.downward@cancer.org.uk Michael J Seckl, Lung Cancer Biology Group, Cancer Research UK, Cyclotron Building, Imperial College London, Hammersmith Hospitals Campus, Du Cane Road, London, UK. Tel.: +44 20 8846 1421; Fax: +44 20 8383 5577; E-mail: m.seckl@imperial.ac.uk Received 23 September 2005; Accepted 29 May 2006; Published online 29 June 2006. |
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| Abstract |
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| 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-XL, 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, PKC and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKC or S6K2 abolishes FGF-2-mediated survival. In contrast, overexpression of PKC increases XIAP and Bcl-XL levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-XL 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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| Keywords: B-Raf, PKC, S6K2, survival, SCLC |
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