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

Olivier E Pardo; Claudia Wellbrock; Umme K Khanzada; Muriel Aubert; Imanol Arozarena; Sally Davidson; Frances Bowen; Peter J Parker; V V Filonenko; Ivan T Gout; Neil Sebire; Richard Marais; Julian Downward; Michael J Seckl

doi:10.1038/sj.emboj.7601198

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

EMBO J. 2006 Jul 12;25(13):3078-88. doi: 10.1038/sj.emboj.7601198. Epub 2006 Jun 29.

Authors

Olivier E Pardo¹, Claudia Wellbrock, Umme K Khanzada, Muriel Aubert, Imanol Arozarena, Sally Davidson, Frances Bowen, Peter J Parker, V V Filonenko, Ivan T Gout, Neil Sebire, Richard Marais, Julian Downward, Michael J Seckl

Affiliation

¹ Lung Cancer Biology Group, Cancer Research UK, Imperial College London, Hammersmith Hospitals Campus, Du Cane Road, London, UK.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Apoptosis / physiology*
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
bcl-X Protein / metabolism

Substances

Antineoplastic Agents
X-Linked Inhibitor of Apoptosis Protein
bcl-X Protein
Fibroblast Growth Factor 2
Etoposide
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf
Ribosomal Protein S6 Kinases, 70-kDa
ribosomal protein S6 kinase, 70kD, polypeptide 2
Protein Kinase C-epsilon
Extracellular Signal-Regulated MAP Kinases