Cisplatin and TNF-alpha downregulate transcription of Bcl-xL in murine malignant mesothelioma cells.
Malignant mesothelioma (MM) is an aggressive and highly chemo-resistant tumour. In this study, we examined cisplatin-induced apoptosis in mouse models of this disease and investigated the role of constitutive and inducible expression of apoptosis related genes in this process. All of the four mouse MM cell lines examined expressed Bax, Bcl-xL, c-Myc, and caspase-3 but not Bcl-2. Cisplatin-induced apoptosis characterised by DNA fragmentation and cell death while caspase-3/7 was activated in 3 of 4 cell lines. Quantitation of basal gene expression showed significant differences but there was no correlation between single genes and cisplatin sensitivity. In the AC29 and AB1 models, both cisplatin and TNF-alpha downregulated Bcl-xL gene expression, indicating that this gene was a common transcriptional target in these cells. The findings of the present study provide insights into apoptotic mechanisms in mesothelioma cells and show similar patterns of gene expression to that reported in the human disease.
Fox
Simon A
SA
Pharmacogenetics Laboratory, School of Pharmacy, Curtin University of Technology and West Australian Biomedical Research Institute, Bentley, WA, Australia. S.Fox@curtin.edu.au
Kusmiaty
Loh
Suzanne S W
SS
Dharmarajan
Arun M
AM
Garlepp
Michael J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D014157:Transcription Factors / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*; D051020:bcl-X Protein / Q000378:metabolism*
D000970:Antineoplastic Agents; C494812:Bcl2l1 protein, mouse; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; D002945:Cisplatin