Understanding and overcoming 'the Warburg Effect'
A team of scientists led by Professor Adrian Krainer, Ph.D., of Cold Spring Harbor Laboratory has discovered molecular factors in cancer cells that boost the production of an enzyme that helps alter the cells' glucose metabolism. The altered metabolic state, called the Warburg effect, promotes extremely rapid cell proliferation and tumor growth.
Adrian Krainer, Ph.D.
Discovered eighty years ago by Nobel Prize-winning scientist Otto Warburg, this altered metabolism in cancer cells is most critically mediated by a protein called PK-M2 (pyruvate kinase M2). This is one of two versions - or isoforms - of the enzyme pyruvate kinase, whose other isoform, PK-M1, is harmless.
In a study published online ahead of print in the Proceedings of the National Academy of Sciences, Krainer and colleagues report their discovery of three factors that contribute to high levels of PK-M2 in cancer cells, in part by suppressing production of PK-M1.
"These findings suggest a new way in which cancer's altered glucose metabolism might be targeted for therapeutic benefit," explains Krainer. "Drugs that inhibit these factors and reverse the Warburg effect might work as anti-cancer agents." The study was performed in collaboration with Professor Lewis Cantley, Ph.D., and his colleagues at Harvard Medical School and The Broad Institute, in Cambridge, Mass.
Cancer cells consume glucose at a much higher rate than normal cells, but use very little glucose to produce energy, spending the rest instead on cell-building material. They also produce huge amounts of a byproduct called lactate. PK-M2, which facilitates this alternate metabolic lifestyle in cancer cells, was recently shown by the Cantley laboratory to be critical for tumor formation and growth.
This isoform and its non-cancerous counterpart PK-M1, which is found only in normal cells, both arise from the same gene, PK-M, via alternative splicing, a process that allows a single gene to produce multiple proteins. The initial RNA copy of a gene's DNA includes unnecessary pieces called introns that are first spliced out. The remaining bits, called exons, can be stitched back together in different ways by the cell's splicing machinery to form different RNAs that can then give rise to different proteins.