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Interferon-gamma modulates a p53-independent apoptotic pathway and apoptosis-related gene expression
N K Ossina1, A Cannas, V C Powers
1LXR Biotechnology Inc., Richmond, California 94804, USA.
Abstract:
Interferon (IFN)-gamma increases the sensitivity of tumor cell lines, many of which are p53 mutants, to tumor necrosis factor-alpha-mediated and anti-Fas antibody-mediated cell death. To better understand the mechanism of IFN-gamma action in modulating the cell death response independently of p53 function, we analyzed the death of the human colon adenocarcinoma cell line, HT-29, following treatment with IFN-gamma and various cytotoxic agents. Here we show that IFN-gamma modulates cell death by sensitizing the cells to killing by numerous pro-apoptotic stimuli but not pro-necrotic stimuli. Furthermore, we show that select genes from several important apoptosis-related gene families are induced by IFN-gamma, including the apoptosis-signaling receptors CD95 (Fas/APO-1) and TNFR 1 and interleukin-1beta-converting enzyme (Ice) family members Ice, CPP32 (Yama, apopain), ICErel-II (TX, Ich-2), Mch-3 (ICE-LAP3, CMH-1), Mch-4, and Mch-5 (MACH, FLICE). Of the bcl-2 family members, IFN-gamma directly induced bak but notably not bax, which is activated by p53. The IFN-responsive transcriptional activator interferon regulatory factor-1 was also strongly induced and translocated into the nucleus following IFN-gamma treatment. We propose that IFN-gamma modulates a p53-independent apoptotic pathway by both directly and indirectly inducing select apoptosis-related genes.
Insights
Interferon-gamma (IFN-gamma) enhances cancer cell death by sensitizing them to apoptosis, independent of p53 function. This involves inducing key apoptosis-related genes, revealing a novel therapeutic pathway.
Area of Science:
- Molecular Biology
- Immunology
- Cancer Research
Background:
- Interferon-gamma (IFN-gamma) is known to increase tumor cell sensitivity to death receptor-mediated apoptosis.
- Many tumor cell lines harbor p53 mutations, necessitating an understanding of p53-independent cell death mechanisms.
Purpose of the Study:
- To elucidate the mechanism by which IFN-gamma modulates p53-independent cell death pathways.
- To identify specific apoptosis-related genes regulated by IFN-gamma.
Main Methods:
- Treatment of human colon adenocarcinoma cell line HT-29 with IFN-gamma and cytotoxic agents.
- Analysis of cell death responses (apoptotic vs. necrotic).
- Gene expression analysis of apoptosis-related gene families (e.g., caspases, Bcl-2 family, transcription factors).
Main Results:
- IFN-gamma sensitized cells to pro-apoptotic stimuli but not pro-necrotic stimuli.
- IFN-gamma induced apoptosis-signaling receptors (CD95, TNFR1) and several caspase family members (ICE, CPP32, ICErel-II, Mch-3, Mch-4, Mch-5).
- IFN-gamma directly induced Bak but not p53-activated Bax, and strongly induced interferon regulatory factor-1 (IRF-1).
Conclusions:
- IFN-gamma activates a p53-independent apoptotic pathway in cancer cells.
- This pathway involves the induction of specific apoptosis-related genes, including death receptors, caspases, and IRF-1.
- IFN-gamma's ability to sensitize cells to apoptosis offers potential for novel cancer therapies.