Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence and tumor growth in a dominant negative manner [Molecular Bases of Disease]

February 3rd, 2014 by Iqbal, M. A., Siddiqui, F. A., Chaman, N., Gupta, V., Kumar, B., Gopinath, P., Bamezai, R. N. K. .

The present study was designed to examine the functional relevance of two heterozygous mutations (H391Y and K422R), observed earlier by us in Bloom Syndrome (BS) condition. Cells stably expressing exogenous wild- or mutant-PKM2 (K422R or H391Y) or co-expressing both wild 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, compared to cells expressing either wild 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 these 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; also evidencing for the first time the possible predisposition of BS patients with impaired PKM2 activity to cancer, and the importance of studying genetic variations in PKM2 in future to understand their relevance in cancer in general.
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