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TGF beta 1 kills lymphoma cells using mitochondrial apoptotic pathway with the help of caspase-8
Gabor Barna1, Anna Sebestyén, Christos C Chinopoulos
11st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Abstract:
It is a known paradox that many TGF beta 1-producing tumor cells are resistant to this, otherwise, inhibitory cytokine. In a lymphoma of B-cell origin exogenous TGF beta 1 was able to induce apoptosis, suggesting that the apoptosis program can be switched on. The apoptosis induction was independent of the death receptors but dependent on mitochondrial pathway and caspase-3. Probably due to the weak starting signal, caspase-3 further activated caspase-8 which, through the Bid cleavage and Bax translocation into the mitochondria, provided an autocatalytic support for the apoptotic program. There is a time-gat between the early activation of Smad-dependent TIEG and the accumulation of ROS, therefore other participants that start the increase in mitochondrial membrane permeability should be identified.
Insights
Tumor cells producing TGF-beta 1 can resist its effects. However, in B-cell lymphoma, TGF-beta 1 initiated apoptosis via the mitochondrial pathway and caspase-3, suggesting a switchable cell death program.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Tumor cells producing TGF-beta 1 often exhibit resistance to its inhibitory effects, a known paradox in cancer research.
- Understanding the mechanisms of TGF-beta 1 resistance and sensitivity is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the mechanism by which exogenous TGF-beta 1 induces apoptosis in B-cell lymphoma.
- To elucidate the specific pathways involved in TGF-beta 1-mediated apoptosis, including the roles of death receptors, mitochondria, and caspases.
Main Methods:
- Treatment of B-cell lymphoma cells with exogenous TGF-beta 1.
- Analysis of apoptosis induction, cell death pathways (death receptor vs. mitochondrial), and caspase activation (caspase-3, caspase-8).
- Assessment of Bid cleavage, Bax translocation, and mitochondrial membrane permeability.
Main Results:
- Exogenous TGF-beta 1 successfully induced apoptosis in B-cell lymphoma cells.
- Apoptosis induction was independent of death receptors but critically dependent on the mitochondrial pathway and caspase-3 activation.
- Caspase-3 further activated caspase-8, leading to Bid cleavage and Bax translocation, which supported the apoptotic program via an autocatalytic loop.
- A time gap was observed between early Smad-dependent TIEG activation and ROS accumulation, indicating other factors initiating mitochondrial membrane permeability.
Conclusions:
- The apoptosis program can be activated in TGF-beta 1-resistant B-cell lymphoma cells.
- TGF-beta 1-induced apoptosis in this context primarily utilizes the mitochondrial pathway, involving caspase-3 and caspase-8.
- Further research is needed to identify the early participants that increase mitochondrial membrane permeability during TGF-beta 1-induced apoptosis.