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Inhibitor of apoptosis proteins are regulated by tumour necrosis factor‐α in malignant pleural mesothelioma
Author(s) -
Gordon GJ,
Mani M,
Mukhopadhyay L,
Dong L,
Yeap BY,
Sugarbaker DJ,
Bueno R
Publication year - 2007
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2120
Subject(s) - xiap , inhibitor of apoptosis , survivin , tumor necrosis factor alpha , cancer research , pyrrolidine dithiocarbamate , apoptosis , programmed cell death , biology , cisplatin , medicine , immunology , nf κb , caspase , chemotherapy , biochemistry
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‐α) 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‐κB. Co‐incubation of MPM cells with TNF‐α and pyrrolidine dithiocarbamate (PDTC), an NF‐κB inhibitor, prevented TNF‐mediated up‐regulation of IAP gene expression levels. In survival studies, TNF‐α was not toxic to MPM cells at any concentration examined. However, MPM cells exposed to TNF‐α 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‐α 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. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.