PP2A mediates apoptosis or autophagic cell death in multiple myeloma cell lines
Hang Zhou1, Wei Luo2, Chao Zeng3
1Department of Chemotherapy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Abstract:
The crosstalk between apoptosis and autophagy contributes to tumorigenesis and cancer therapy. The process by which BetA (betulinic acid), a naturally occurring triterpenoid, regulates apoptosis and autophagy as a cancer therapy is unclear. In this study, we show for the first time that protein phosphatase 2A (PP2A) acts as a switch to regulate apoptosis and autophagic cell death mediated by BetA. Under normal conditions, caspase-3 is activated by the mitochondrial pathway upon BetA treatment. Activated caspase-3 cleaves the A subunit of PP2A (PP2A/A), resulting in the association of PP2A and Akt. This association inactivates Akt to initiate apoptosis. Overexpression of Bcl-2 attenuates the mitochondrial apoptosis pathway, resulting in caspase-3 inactivation and the dissociation of PP2A and Akt. PP2A isolated from Akt binds with DAPK to induce autophagic cell death. Meanwhile, in vivo tumor experiments have demonstrated that BetA initiates different types of cell death in a myeloma xenograft model. Thus, PP2A can shift myeloma cells from apoptosis to autophagic cell death. These findings have important implications for the therapeutic application of BetA, particularly against apoptosis-resistant cancers.
Insights
Betulinic acid (BetA) triggers cancer cell death by regulating protein phosphatase 2A (PP2A). PP2A switches myeloma cells between apoptosis and autophagic cell death, offering new therapeutic strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Apoptosis and autophagy crosstalk is crucial in cancer development and treatment.
- Betulinic acid (BetA) is a natural triterpenoid with potential anticancer properties, but its mechanism regulating apoptosis and autophagy remains unclear.
Purpose of the Study:
- To elucidate the role of protein phosphatase 2A (PP2A) in mediating BetA-induced apoptosis and autophagic cell death.
- To investigate the molecular mechanisms by which BetA regulates these cell death pathways.
Main Methods:
- Cell-based assays to study apoptosis and autophagy.
- Western blotting and protein interaction studies.
- In vivo studies using a myeloma xenograft model.
Main Results:
- BetA treatment activates caspase-3, leading to PP2A/A cleavage and Akt inactivation, initiating apoptosis.
- Bcl-2 overexpression inhibits apoptosis, causing PP2A to bind DAPK and induce autophagic cell death.
- In vivo experiments confirmed BetA induces distinct cell death types in myeloma xenografts.
Conclusions:
- PP2A acts as a critical switch, directing BetA-induced cell death towards either apoptosis or autophagy in myeloma cells.
- These findings highlight PP2A's regulatory role in BetA's anticancer effects and suggest potential for treating apoptosis-resistant cancers.
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