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Impaired TNFalpha-induced A20 expression in E1A/Ras-transformed cells
1The Campbell Family Institute of Breast Cancer Research, Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, 620 University Avenue, Toronto, Ontario, Canada. hhuang@mail.cjcu.edu.tw
British Journal of Cancer
|October 15, 2009
Summary
Tumour necrosis factor (TNF) can kill transformed cells, but survival signals often protect them. This study found that impaired A20 induction in E1A/Ras-transformed cells makes them sensitive to TNF-induced apoptosis.
Area of Science:
- Cellular biology
- Molecular oncology
- Apoptosis research
Background:
- Tumour necrosis factor (TNF) triggers cell death pathways and can eliminate transformed cells.
- However, TNF also activates survival signals, like NF-kappaB, which promote anti-apoptotic gene expression and protect cells from TNF-induced toxicity.
Purpose of the Study:
- To investigate the factors determining TNF sensitivity in transformed cells.
- To compare TNF-induced apoptosis in wild-type and E1A/Ras-transformed mouse embryonic fibroblasts (MEFs).
Main Methods:
- Compared TNF-induced apoptosis in wild-type and E1A/Ras-transformed MEFs.
- Analyzed TNF signaling pathways, including NF-kappaB, A20 induction, p53 stabilization, and p38/JNK signaling.
- Assessed A20 promoter activity and the role of Bcl-3 in E1A/Ras MEFs.
Main Results:
- E1A/Ras-transformed MEFs, unlike wild-type MEFs, were susceptible to TNF-induced apoptosis.
- A20 induction was abolished in E1A/Ras-transformed cells despite intact NF-kappaB signaling.
- Reintroducing A20 rescued these cells from TNF-induced death and reduced FADD/caspase-8 complex formation.
Conclusions:
- Impaired induction of the survival factor A20 is a key determinant of TNF sensitivity in E1A/Ras-transformed cells.
- Targeting specific survival factors like A20 could be a strategy to enhance TNF-induced apoptosis in cancer therapy.
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