title: Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells.
abstract: The mitochondrial release of cytochrome c and Smac/DIABLO has been implicated in the activation of apoptosis in response to cell stress. Smac promotes cytochrome c-induced activation of caspases by sequestering the inhibitor of apoptosis protein (IAP) family of potent caspase suppressors. Differential release from mitochondria of cytochrome c and Smac can occur, but the underlying mechanism and physiological significance of this are unclear. Here we show that the mechanism by which fibroblast growth factor 2 (FGF-2) protects small cell lung cancer (SCLC) cells from etoposide-induced cell death involves inhibition of Smac release but not of cytochrome c release. This process is MEK dependent and correlates with an increased expression of XIAP and cellular IAP-1, mediated principally through translational regulation. Exogenous expression of XIAP is sufficient to inhibit caspase 9 activation, Smac release, and cell death induced by etoposide. Prevention of the FGF-2-promoted increase in levels of functional IAPs by RNA interference or the cell-permeant Smac amino-terminal peptide blocked FGF-2-induced protection. FGF-2 can thus protect SCLC cells from chemotherapeutic drugs by modulating IAP levels via posttranscriptional regulation, providing a mechanism for postmitochondrial survival signaling by the MEK/mitogen-activated protein kinase pathway.
authors.affiliation: Lung Cancer Biology Group, Cancer Research UK, London SW3, United Kingdom.
authors.forename: Olivier E
authors.initials: OE
authors.lastname: Pardo
authors.forename: Adeline
authors.initials: A
authors.lastname: Lesay
authors.forename: Alexandre
authors.initials: A
authors.lastname: Arcaro
authors.forename: Rita
authors.initials: R
authors.lastname: Lopes
authors.forename: Bee Ling
authors.initials: BL
authors.lastname: Ng
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Warne
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
authors.forename: Teresa D
authors.initials: TD
authors.lastname: Tetley
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Lemoine
authors.forename: Huseyin
authors.initials: H
authors.lastname: Mehmet
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free; D045304:Cytochromes c / Q000378:metabolism; D004789:Enzyme Activation; D005047:Etoposide / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048369:MAP Kinase Kinase 1; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D016895:Culture Media, Serum-Free; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D016222:Fibroblast Growth Factor 2; D005047:Etoposide; D045304:Cytochromes c; D017346:Protein Serine-Threonine Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020169:Caspases