HOUSTON -- The embryonic enzyme pyruvate kinase M2 (PKM2) has a well-established role in metabolism and is highly expressed in human cancers. Now, a team led by researchers at the University of Texas MD Anderson Cancer Center reports in advance online publication of the journal Nature that PKM2 has important non-metabolic functions in cancer formation.
"Our research shows that although PKM2 plays an important role in cancer metabolism, this enzyme also has an unexpected pivotal function it regulates cell proliferation directly," said senior author Zhimin Lu, M.D., Ph.D., associate professor in the Department of Neuro-Oncology at MD Anderson. "Basically, PKM2 contributes directly to gene transcription for cell growth a finding that was very surprising."
The researchers demonstrated that PKM2 is essential for epidermal growth factor receptor (EGFR)promoted beta-catenin activation, which leads to gene expression, cell growth and tumor formation.
They also discovered that levels of beta-catenin phosphorylation and PKM2 in the cell nucleus are correlated with brain tumor malignancy and prognosis and might serve as biomarkers for customized treatment with Src inhibitors.
In response to epidermal growth factor (EGF), the team found, PKM2 moves into the cell nucleus and binds to beta-catenin that has had a phosphate atom and three oxygen atoms attached at a specific spot called Y333 by the protein c-Src. This binding is essential for beta-catenin activation and expression of downstream gene cyclin D1. This newly discovered way to regulate beta-catenin is independent of the Wnt signaling pathway previously known to activate beta-catenin.
One enzyme controls both cancer cell metabolism and cell cycle progression
In metabolism, PKM2 enhances oxygen-driven processing of sugar known as aerobic glycolysis or the Warburg effect found in tumor cells.
"Cancer cell metabolism and cancer cell cycle prog
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University of Texas M. D. Anderson Cancer Center