Inhibitor of apoptosis proteins are regulated by tumour necrosis factor-alpha in malignant pleural mesothelioma

J Pathol. 2007 Mar;211(4):439-46. doi: 10.1002/path.2120.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / analysis
  • Adaptor Proteins, Signal Transducing / genetics
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • Inhibitor of Apoptosis Proteins / analysis
  • Inhibitor of Apoptosis Proteins / genetics*
  • Mesothelioma / blood
  • Mesothelioma / chemistry
  • Mesothelioma / genetics*
  • Microtubule-Associated Proteins / analysis
  • Microtubule-Associated Proteins / genetics
  • NF-kappa B / genetics
  • Neoplasm Proteins / analysis
  • Neoplasm Proteins / genetics*
  • Pleural Neoplasms / blood
  • Pleural Neoplasms / chemistry
  • Pleural Neoplasms / genetics*
  • RNA, Messenger / analysis
  • RNA, Neoplasm / analysis
  • Survivin
  • Transcription, Genetic / genetics
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / genetics*
  • Up-Regulation / genetics
  • X-Linked Inhibitor of Apoptosis Protein / analysis
  • X-Linked Inhibitor of Apoptosis Protein / genetics


  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • BIRC5 protein, human
  • BIRC7 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • NF-kappa B
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Survivin
  • Tumor Necrosis Factor-alpha
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Cisplatin