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The metastasis suppressor gene C33/CD82/KAI1 induces apoptosis through reactive oxygen intermediates
Nicole Schoenfeld1, Manuel K A Bauer, Stefan Grimm
1Max-Planck-Institute for Biochemistry, Martinsried, Germany.
Abstract:
Here we describe the isolation of C33/CD82/KAI1 in a screen for apoptosis-inducing genes. C33 is a gene that is downregulated in many metastatic tumor cells and the expression of which can attenuate the process of metastases formation in a variety of tumors. In accordance, we observed cell death induction by C33 in many different cell types. C33 seems to promote cell death by the generation of reactive oxygen intermediates (ROIs). These ROIs, however, are not derived from the mitochondrial respiratory chain as in most other scenarios leading to apoptosis. We observed that C33 renders cells sensitive to ROIs by causing the specific release of the intracellular antioxidant glutathione (GSH) from cells. Moreover, C33 activates the GTPase Cdc42, which mediates GSH release and apoptosis induction and allows to detect the formation of ROIs.
Insights
The gene C33 (also known as CD82/KAI1) induces apoptosis by promoting reactive oxygen intermediates (ROIs) generation. It achieves this by causing glutathione (GSH) release, independent of mitochondrial pathways.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- C33/CD82/KAI1 is a gene frequently downregulated in metastatic cancers.
- Its expression is linked to reduced metastasis formation across various tumor types.
- Apoptosis-inducing genes are crucial targets for cancer therapy.
Purpose of the Study:
- To investigate the mechanism by which C33 induces apoptosis.
- To identify the signaling pathways involved in C33-mediated cell death.
- To explore the role of reactive oxygen intermediates (ROIs) in C33-induced apoptosis.
Main Methods:
- Gene screening to identify apoptosis-inducing genes.
- Cell viability assays across different cell types.
- Measurement of reactive oxygen intermediates (ROIs) and glutathione (GSH) levels.
- Analysis of GTPase Cdc42 activation.
Main Results:
- C33 expression induced cell death in multiple cell types.
- C33-mediated apoptosis involved reactive oxygen intermediates (ROIs) generation.
- ROIs were not derived from the mitochondrial respiratory chain.
- C33 triggered the release of intracellular glutathione (GSH), sensitizing cells to ROIs.
- C33 activated the GTPase Cdc42, which mediated GSH release and apoptosis.
Conclusions:
- C33/CD82/KAI1 is a novel apoptosis-inducing gene.
- C33 promotes cell death via a non-mitochondrial ROI generation pathway.
- GSH release and Cdc42 activation are key mechanisms in C33-induced apoptosis.
- C33 represents a potential therapeutic target for metastatic cancers.