Metabolic Protein Plays Unexpected Role

Photo: Brain tumour

Researchers found point to possible
personalised brain tumour
therapy with Src inhibitors;
© Steidl

"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 Doctor Zhimin Lu. "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 tumour formation. They also discovered that levels of beta-catenin phosphorylation and PKM2 in the cell nucleus are correlated with brain tumour malignancy and prognosis and might serve as biomarkers for customised 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 signalling pathway previously known to activate beta-catenin. In metabolism, PKM2 enhances oxygen-driven processing of sugar known as aerobic glycolysis or the Warburg effect found in tumour cells.

"Cancer cell metabolism and cancer cell cycle progression, which are essential for tumour formation, are conventionally thought to be regulated primarily by distinct signalling complexes," Lu said. The new findings integrate the two major mechanisms for regulating cancer cell growth by a key metabolic enzyme. "These two important regulatory processes are under the control of pyruvate kinase M2."

The researchers analysed brain tumours in 84 patients who had been treated with radiation and chemotherapy after surgery. Those who had low beta-catenin Y333 phosphorylation or low expression of PKM2 in the nucleus (28 cases each) had a median survival of 185 weeks and 130 weeks, respectively.

Findings include:

• PKM2-dependent beta-catenin activation is instrumental in EGFR-promoted tumour cell proliferation and brain tumour development.
• c-Src activity, beta-catenin Y333 phosphorylation, and PKM2 nuclear accumulation are positively correlated in human glioblastoma specimens.
• Levels of beta-catenin phosphorylation and nuclear PKM2 are correlated with grades of glioma malignancy and prognosis.; Source: The University of Texas MD Anderson Cancer Centre