PP2A mediates apoptosis or autophagic cell death in multiple myeloma cell lines
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Hang Zhou1,*, Wei Luo2,*, Chao Zeng3,*, Yu Zhang5, Liyang Wang1, Wenxiu Yao1 and Chunlai Nie1,4
1Department of Chemotherapy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
2Department of Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
3Department of Gastroenterology, the Third People’s Hospital of Chengdu, Chengdu, China
4Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
5Department of Oncology, Guizhou People’s Hospital, Guizhou, China
*These authors have contributed equally to this work
Wenxiu Yao, email: [email protected]
Chunlai Nie, email: [email protected]
Keywords: chemoresistance, autophagy, apoptosis, Beclin-1, PP2A
Received: February 08, 2017 Accepted: June 27, 2017 Published: August 23, 2017
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.
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