Inhibitor of apoptosis proteins are regulated by tumour necrosis factor-alpha in malignant pleural mesothelioma
Saturday, January 27th, 2007.
The Journal of Pathology. 2007 Mar;211(4):439-46. [Link]
GJ Gordon 1 *, M Mani 1, L Mukhopadhyay 1, L Dong 1, BY Yeap 2, DJ Sugarbaker 1, R Bueno 1
1The 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
2Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114, USA. email: GJ Gordon (ggordon@partners.org)
*Correspondence to GJ Gordon, PhD, Brigham and Women’s Hospital, BLI Bldg, Room 137, 221 Longwood Ave, Boston, MA 02115, USA.
Abstract
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.
Glossary
- prognosis
- (prog-no-sis) a prediction of the course of disease; the outlook for the cure of the patient. For example, women with breast cancer that was detected early and who received prompt treatment have a good prognosis.
- oncology
- (on-call-o-jee) the branch of medicine concerned with the diagnosis and treatment of cancer.
- nucleus
- (new-clee-us) the center of a cell where the DNA is housed and replicated. Studying the size and shape of a cell's nucleus under the microscope can help pathologists distinguish cancer cells from benign cells.
- gene
- a segment of DNA that contains information on hereditary characteristics such as hair color, eye color, and height, as well as susceptibility to certain diseases. Women who have BRCA1 or BRCA2 gene mutations (defects) have an inherited tendency to develop breast cancer.
- cell
- the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.
- mesothelioma
- a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.
- apoptosis
- a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.
