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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins
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Carcinoma, Small Cell / metabolism*
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Carcinoma, Small Cell / pathology
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Carrier Proteins / metabolism*
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Caspases / metabolism
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Cell Death / physiology
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Cell Line, Tumor
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Culture Media, Serum-Free
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Cytochromes c / metabolism
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Enzyme Activation
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Etoposide / metabolism
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Fibroblast Growth Factor 2 / metabolism*
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Gene Expression Regulation, Neoplastic
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Humans
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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MAP Kinase Kinase 1
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Mitochondria / metabolism*
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Mitochondrial Proteins / metabolism*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Nucleic Acid Synthesis Inhibitors / metabolism
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Protein Biosynthesis*
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Protein Serine-Threonine Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism*
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X-Linked Inhibitor of Apoptosis Protein
Substances
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Apoptosis Regulatory Proteins
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Carrier Proteins
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Culture Media, Serum-Free
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DIABLO protein, human
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Nucleic Acid Synthesis Inhibitors
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Proteins
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human
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Fibroblast Growth Factor 2
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Etoposide
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Cytochromes c
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Protein Serine-Threonine Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Caspases