期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 12, 页码 8098-8105出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.515742
关键词
Cancer Tumor Promoter; Enzyme Mutation; Glycolysis; Pyruvate Kinase; Tumor Metabolism; Bloom Syndrome; Dominant Negative Mutation; PKM2
资金
- University Grants Commission (UGC), Government of India
- UGC
Background: We earlier reported novel mutations in PKM2 that reduce its activity. Results: These mutations promoted cancer features and tumor growth in a dominant negative manner. Conclusion: Impaired PKM2 activity due to mutations benefits cancer. Significance: This study provides the first evidence linking natural mutations in PKM2 with cancer. The present study was designed to examine the functional relevance of two heterozygous mutations (H391Y and K422R), observed earlier by us in the Bloom syndrome condition. Cells stably expressing exogenous wild-type or mutant PKM2 (K422R or H391Y) or co-expressing both wild type and mutant (PKM2-K422R or PKM2-H391Y) were assessed for cancer metabolism and tumorigenic potential. Interestingly, cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism as compared with cells expressing either wild-type or mutant PKM2 independently. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation, and tumor growth. These observations signify the dominant negative nature of mutations. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. Such a dominant negative impaired function of PKM2 in tumor development is not known; this study demonstrates for the first time the possible predisposition of Bloom syndrome patients with impaired PKM2 activity to cancer and the importance of studying genetic variations in PKM2 in the future to understand their relevance in cancer in general.
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