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 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.
Pardo
Olivier E
OE
Lung Cancer Biology Group, Cancer Research UK, Imperial College London, Hammersmith Hospitals Campus, Du Cane Road, London, UK.
Wellbrock
Claudia
C
Khanzada
Umme K
UK
Aubert
Muriel
M
Arozarena
Imanol
I
Davidson
Sally
S
Bowen
Frances
F
Parker
Peter J
PJ
Filonenko
V V
VV
Gout
Ivan T
IT
Sebire
Neil
N
Marais
Richard
R
Downward
Julian
J
Seckl
Michael J
MJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000502:physiology*; D048493:Proto-Oncogene Proteins B-raf / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000502:physiology*; D015398:Signal Transduction; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D051636:X-Linked Inhibitor of Apoptosis Protein; D051020:bcl-X Protein; D016222:Fibroblast Growth Factor 2; D005047:Etoposide; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D038762:Ribosomal Protein S6 Kinases, 70-kDa; C448959:ribosomal protein S6 kinase, 70kD, polypeptide 2; D051744:Protein Kinase C-epsilon; D048049:Extracellular Signal-Regulated MAP Kinases