title: Fibroblast growth factor-2 induces translational regulation of Bcl-XL and Bcl-2 via a MEK-dependent pathway: correlation with resistance to etoposide-induced apoptosis.
abstract: The involvement of fibroblast growth factor-2 (FGF-2) in the biology of small cell lung cancer (SCLC) has not previously been investigated. Here we report that FGF-2 prevented etoposide-induced apoptosis in H-510 SCLC cells. Phosphatidylinositol 3-kinase/protein kinase B signaling did not mediate this effect because FGF-2 failed to activate phosphatidylinositol 3-kinase or protein kinase B. In contrast, the mitogen-activated extracellularly regulated kinase kinase (MEK) was crucial for this response because its inhibition abolished the prosurvival properties of FGF-2. Moreover, in H-69 SCLC cells, the failure of FGF-2 to prevent etoposide-induced apoptosis correlated with uncoupling from MEK activation. However, the introduction of an activated MEK rendered these cells resistant to etoposide killing. Cell rescue relied on de novo protein synthesis, and the anti-apoptotic proteins Bcl-X(L) and Bcl-2 were up-regulated in a MEK-dependent fashion within 4 h of FGF-2 treatment. Contrary to previous reports, we found that this up-regulation occurred at the translational rather than the transcriptional level. Indeed, actinomycin D failed to prevent up-regulation of Bcl-X(L) and Bcl-2, and FGF-2 did not increase the mRNA levels or the stability of these proteins. The induction of the pro-apoptotic protein Bad by etoposide was also blocked by FGF-2 in a MEK-dependent fashion. Thus, MEK/extracellularly regulated kinase signaling is critical in the coordinate modulation of both pro- and anti-apoptotic Bcl-2 family members by FGF-2.
authors.affiliation: Cancer Research United Kingdom Lung Cancer Biology Group and the Medical Research Council Clinical Sciences Centre, Hammersmith Campus of Imperial College, Ducane Road, London W12 0NN, United Kingdom.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Pardo
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
authors.forename: Giovanni
authors.initials: G
authors.lastname: Salerno
authors.forename: Selina
authors.initials: S
authors.lastname: Raguz
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
mesh_terms: D017304:Annexin A5 / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D003609:Dactinomycin / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051020:bcl-X Protein
chemical_list: D017304:Annexin A5; D053148:Caspase 3; D020169:Caspases; D003609:Dactinomycin; D004791:Enzyme Inhibitors; D005047:Etoposide; D016222:Fibroblast Growth Factor 2; D005419:Flavonoids; D048728:MAP Kinase Kinase Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; C494811:BCL2L1 protein, human; C482576:MAP3K1 protein, human; C505407:CASP3 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one