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PMID: 14560006 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells.

Molecular and cellular biology ·Vol. 23 ·No. 21 ·2003-11-00 ·Pages 7600-10

Pardo OE, Lesay A, Arcaro A, Lopes R, Ng BL, Warne PH, McNeish IA, Tetley TD, Lemoine NR, Mehmet H, Seckl MJ, Downward J

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.

MeSH Terms
Apoptosis/physiology Apoptosis Regulatory Proteins Carcinoma, Small Cell/metabolism,pathology Carrier Proteins/metabolism Caspases/metabolism Cell Death/physiology Cell Line, Tumor Culture Media, Serum-Free Cytochromes c/metabolism Enzyme Activation Etoposide/metabolism Fibroblast Growth Factor 2/metabolism Gene Expression Regulation, Neoplastic Humans Inhibitor of Apoptosis Proteins Intracellular Signaling Peptides and Proteins MAP Kinase Kinase 1 Mitochondria/metabolism Mitochondrial Proteins/metabolism Mitogen-Activated Protein Kinase Kinases/metabolism Nucleic Acid Synthesis Inhibitors/metabolism Protein Biosynthesis Protein Serine-Threonine Kinases/metabolism Proteins/genetics,metabolism X-Linked Inhibitor of Apoptosis Protein
Chemicals
Apoptosis Regulatory Proteins Carrier Proteins Culture Media, Serum-Free DIABLO protein, human Inhibitor of Apoptosis Proteins Intracellular Signaling Peptides and Proteins Mitochondrial Proteins Nucleic Acid Synthesis Inhibitors Proteins X-Linked Inhibitor of Apoptosis Protein XIAP protein, human Fibroblast Growth Factor 2 Etoposide Cytochromes c Protein Serine-Threonine Kinases MAP Kinase Kinase 1 MAP2K1 protein, human Mitogen-Activated Protein Kinase Kinases Caspases
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Pardo Olivier E
Lung Cancer Biology Group, Cancer Research UK, London SW3, United Kingdom.
Lesay Adeline
Arcaro Alexandre
Lopes Rita
Ng Bee Ling
Warne Patricia H
McNeish Iain A
Tetley Teresa D
Lemoine Nicholas R
Mehmet Huseyin
Seckl Michael J
Downward Julian
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.21.7600-7610.2003
Published
2003-11-00
Pages
7600-10
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC207633
Subset
IM
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1128/MCB.23.21.7600-7610.2003 PMC Full Text View journal details
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