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Study helps explain fundamental process of tumor growth
Date:3/12/2008

se-hungry tumor cells, the areas of high glucose uptake are displayed dramatically on the PET scan.

Using a novel proteomic screen to identify new phosphotyrosine binding proteins, Cantley and his colleagues first determined that PKM2 can bind to phosphotyrosine-containing peptides. We observed that in contrast to the forms of pyruvate kinase found in most normal adult tissues, only PKM2, which is found in fetal cells, interacted with phosphotyrosine, explains Cantley. This finding was particularly interesting because previous reports had shown that this M2 form was the pyruvate kinase form used by all cancer cells.

In order to understand the implications of this discovery, Cantley and his coauthors next embarked upon experiments to evaluate the importance of PKM2 to cancer cells. Reasoning that tumor tissue switches pyruvate kinase expression from an adult M1 isoform to the embryonic M2 isoform, they performed immunoblotting and immunohistochemistry analysis of numerous cancer cell lines, breast cancer models and human colon cancer, confirming that PKM2 was the only form of pyruvate kinase found in cancerous tissue.

The authors then knocked down PKM2 expression in human cancer cell lines and expressed the adult M1 form instead. This switch from the fetal M2 form to the adult M1 isoform led to reduced lactate production and increased oxygen consumption a reversal of the Warburg effect.

We were able to show that only cells which express the M2 form of pyruvate kinase and metabolize glucose in the way described by Otto Warburg 80 years ago had the ability to form tumors in mice, notes Cantley. In addition, the investigators demonstrated that it is the ability of PKM2 to interact with phosphotyrosine that enables this form of pyruvate kinase to promote the unique glucose metabolism seen in cancer cells, thereby allowing these cells to make tumors in vivo.

The findings are consistent with the idea that tumor cells prefe
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Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

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