FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2

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 sp...

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Bibliographic Details
Published in:The EMBO journal 2006-07, Vol.25 (13), p.3078-3088
Main 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
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis - physiology
bcl-X Protein - metabolism
Carcinoma, Small Cell - metabolism
Carcinoma, Small Cell - pathology
Cell Line
Cell Line, Tumor
Cell Survival
Drug Resistance, Neoplasm
Etoposide - pharmacology
Extracellular Signal-Regulated MAP Kinases - physiology
Fibroblast Growth Factor 2 - physiology
Humans
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Phosphorylation
Protein Kinase C-epsilon - physiology
Proto-Oncogene Proteins B-raf - physiology
Proto-Oncogene Proteins c-raf - physiology
Ribosomal Protein S6 Kinases, 70-kDa - physiology
Signal Transduction
X-Linked Inhibitor of Apoptosis Protein - metabolism
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Summary: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.
ISSN:0261-4189