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Molecular and Cellular Biology, November 2003, p. 7600-7610, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7600-7610.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Fibroblast Growth Factor 2-Mediated Translational Control of IAPs Blocks Mitochondrial Release of Smac/DIABLO and Apoptosis in Small Cell Lung Cancer Cells

Olivier E. Pardo,1,2 Adeline Lesay,3 Alexandre Arcaro,1 Rita Lopes,4 Bee Ling Ng,1 Patricia H. Warne,2 Iain A. McNeish,4 Teresa D. Tetley,5 Nicholas R. Lemoine,4 Huseyin Mehmet,3 Michael J. Seckl,1* and Julian Downward2*

Lung Cancer Biology Group,1 Molecular Oncology Unit, Cancer Research UK,4 Weston Laboratories, Imperial College London, Hammersmith Campus, London W12 0NN,3 Signal Transduction Laboratory, Cancer Research UK, London W2A 3PX,2 Lung Cell Biology, National Heart and Lung Institute, Imperial College London, Royal Brompton Campus, London SW3, United Kingdom5

Received 21 May 2003/ Returned for modification 16 June 2003/ Accepted 14 July 2003

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.

* Corresponding author. Mailing address for Michael J. Seckl: Lung Cancer Biology Group, Cancer Research UK, Cyclotron Building, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8846-1421. Fax: 44-20-8748-5665. E-mail: mseckl{at}imperial.ac.uk. Mailing address for Julian Downward: Signal Transduction Laboratory, Cancer Research UK, 44 Lincoln's Inn Fields, London W2A 3PX, United Kingdom. Phone: 44-20-7269-3533. Fax: 44-20-7269-3094. E-mail: downward{at}cancer.org.uk.

Molecular and Cellular Biology, November 2003, p. 7600-7610, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7600-7610.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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