Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2

• Published in: Cell research Vol. 27; no. 3; pp. 329 - 351
• Main Authors: Liang, Ji, Cao, Ruixiu, Wang, Xiongjun, Zhang, Yajuan, Wang, Pan, Gao, Hong, Li, Chen, Yang, Fan, Zeng, Rong, Wei, Ping, Li, Dawei, Li, Wenfeng, Yang, Weiwei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2017; Nature Publishing Group
• Subjects: 631/67/1922; 631/80/82/23; 631/80/86/2366; 692/420/755; Amino Acid Sequence; Amino acids; Apoptosis - drug effects; Biomedical and Life Sciences; Brain tumors; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell Biology; Cell Line, Tumor; Cullin Proteins - metabolism; Glioma - metabolism; Glioma - pathology; HSP90 Heat-Shock Proteins - metabolism; Humans; Hydrogen Peroxide - pharmacology; Life Sciences; Mitochondria - drug effects; Mitochondria - metabolism; Original; original-article; Oxidative stress; Oxidative Stress - drug effects; Phosphorylation - drug effects; Phosphothreonine - metabolism; Prognosis; Protein Binding - drug effects; Protein Stability - drug effects; Protein Transport - drug effects; Proteolysis - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pyruvate Kinase - chemistry; Pyruvate Kinase - metabolism; Ubiquitin-Protein Ligases - metabolism; HSP90; PKM2; mitochondria; Bcl2; apoptosis; tumorigenesis; oxidative stress
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2016.159

Pyruvate kinase M2 isoform （PKM2） catalyzes the last step of glycolysis and plays an important role in tumor cell proliferation. Recent studies have reported that PKM2 also regulates apoptosis. However, the mechanisms under- lying such a role of PKM2 remain elusive. Here we show that PKM2 translocates to mitochondria under oxidative stress. In the mitochondria, PKM2 interacts with and phosphorylates Bcl2 at threonine （T） 69. This phosphoryla- tion prevents the binding of Cul3-based E3 ligase to Bcl2 and subsequent degradation of Bcl2. A chaperone protein, HSP90al, is required for this function of PKM2. HSP90al＇s ATPase activity launches a conformational change of PKM2 and facilitates interaction between PKM2 and Bci2. Replacement of wild-type Bcl2 with phosphorylation-de- ficient Bcl2 T69A mutant sensitizes glioma cells to oxidative stress-induced apoptosis and impairs brain tumor for- mation in an orthotopic xenograft model. Notably, a peptide that is composed of the amino acid residues from 389 to 405 of PKM2, through which PKM2 binds to Bcl2, disrupts PKM2-BcI2 interaction, promotes Bcl2 degradation and impairs brain tumor growth. In addition, levels of Bcl2 T69 phosphorylation, conformation-altered PKM2 and Bcl2 protein correlate with one another in specimens of human glioblastoma patients. Moreover, levels of Bcl2 T69 phos- phorylation and conformation-altered PKM2 correlate with both grades and prognosis of glioma malignancy. Our findings uncover a novel mechanism through which mitochondrial PKM2 phosphorylates Bcl2 and inhibits apoptosis directly, highlight the essential role of PKM2 in ROS adaptation of cancer cells, and implicate HSP90-PKM2-Bcl2 axis as a potential target for therapeutic intervention in glioblastoma.