Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence, and tumor growth in a dominant negative manner.
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.
From the National Centre of Applied Human Genetics, School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi, 110067 India.
Mohd Askandar
MA
Iqbal
Farid Ahmad
FA
Siddiqui
Noor
N
Chaman
Vibhor
V
Gupta
Bhupender
B
Kumar
Prakasam
P
Gopinath
Rameshwar N K
RN
Bamezai
D000818:Animals; D001816:Bloom Syndrome / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D006019:Glycolysis; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D020125:Mutation, Missense; D011770:Pyruvate Kinase / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D011770:Pyruvate Kinase
Bloom Syndrome; Cancer Tumor Promoter; Dominant Negative Mutation; Enzyme Mutation; Glycolysis; PKM2; Pyruvate Kinase; Tumor Metabolism