Document Detail

Inhibitor of apoptosis proteins are regulated by tumour necrosis factor-alpha in malignant pleural mesothelioma.
MedLine Citation:
PMID:  17253597     Owner:  NLM     Status:  MEDLINE    
Inhibitor of apoptosis proteins (IAPs) are overexpressed by most neoplasms and promote tumour cell survival after a wide variety of apoptotic stimuli elicited via intrinsic (ie mitochondrial) and extrinsic (ie death receptor) pathways. It has previously been reported that one of these proteins, IAP-1(MIHC/cIAP2), is overexpressed in malignant pleural mesothelioma (MPM) and is responsible for a large degree of the resistance of cultured MPM cells to cisplatin. Subsequent analysis in a larger number of human tumours revealed that additional IAPs (eg IAP-2/MIHB/cIAP1, livin/ML-IAP/KIAP, survivin, and XIAP/MIHA/hILP) are also overexpressed in MPM and, with the exception of IAP-2, have expression patterns that correlate with prognosis. In the present study, potential regulatory mechanisms of IAP genes in MPM were investigated and it was found that tumour necrosis factor-alpha (TNF-alpha) can increase mRNA and protein levels of IAP-1, IAP-2, and XIAP, but not livin or survivin in MPM cell lines (n=4). It was also found that IAP gene expression levels are increased concomitantly with translocation to the nucleus of the TNF-responsive transcription factor NF-kappaB. Co-incubation of MPM cells with TNF-alpha and pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, prevented TNF-mediated up-regulation of IAP gene expression levels. In survival studies, TNF-alpha was not toxic to MPM cells at any concentration examined. However, MPM cells exposed to TNF-alpha were twice as resistant to cisplatin in dose response survival assays compared with unstimulated controls and were found to have a significantly greater fraction of surviving cells at multiple cisplatin concentrations (p<0.0087). Finally, it was found that levels of circulating TNF-alpha were statistically significantly (p=0.031) (median 312.5 pg/ml) higher in MPM patients (n=6) prior to surgical tumour debulking compared with those after surgery (median 0 pg/ml). These results when combined with previous observations by our laboratory and others strongly suggest that IAPs act synergistically with TNF family members to promote survival of MPM tumour cells after exposure to cisplatin and possibly other chemotherapeutic drugs.
G J Gordon; M Mani; L Mukhopadhyay; L Dong; B Y Yeap; D J Sugarbaker; R Bueno
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of pathology     Volume:  211     ISSN:  0022-3417     ISO Abbreviation:  J. Pathol.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-27     Completed Date:  2007-04-24     Revised Date:  2008-05-14    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  England    
Other Details:
Languages:  eng     Pagination:  439-46     Citation Subset:  IM    
Copyright Information:
Copyright (c) 2007 Pathological Society of Great Britain and Ireland.
The Thoracic Surgery Oncology Laboratory and the Division of Thoracic Surgery, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA.
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MeSH Terms
Adaptor Proteins, Signal Transducing / analysis,  genetics
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cisplatin / pharmacology
Gene Expression Regulation, Neoplastic / genetics
Inhibitor of Apoptosis Proteins / analysis,  genetics*
Mesothelioma / blood,  chemistry,  genetics*
Microtubule-Associated Proteins / analysis,  genetics
NF-kappa B / genetics
Neoplasm Proteins / analysis,  genetics*
Pleural Neoplasms / blood,  chemistry,  genetics*
RNA, Messenger / analysis
RNA, Neoplasm / analysis
Transcription, Genetic / genetics
Tumor Necrosis Factor-alpha / blood,  genetics*
Up-Regulation / genetics
X-Linked Inhibitor of Apoptosis Protein / analysis,  genetics
Grant Support
Reg. No./Substance:
0/Adaptor Proteins, Signal Transducing; 0/Antineoplastic Agents; 0/BIRC5 protein, human; 0/BIRC7 protein, human; 0/Inhibitor of Apoptosis Proteins; 0/Microtubule-Associated Proteins; 0/NF-kappa B; 0/Neoplasm Proteins; 0/RNA, Messenger; 0/RNA, Neoplasm; 0/Tumor Necrosis Factor-alpha; 0/X-Linked Inhibitor of Apoptosis Protein; 0/XIAP protein, human; 15663-27-1/Cisplatin

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