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CSHL study identifies potential way to reverse cancer cell metabolism and tumor growth
Date:1/22/2010

t 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.

In the case of the PK-M gene, its RNA undergoes alternative splicing in a mutually exclusive fashion, giving rise to either the M1 or the M2 isoform. Krainer, an expert on alternative splicing, has been focused on understanding how the benign M1 isoform is switched off and the dangerous M2 isoform switched on in cancer cells. His team began by tracking down splicing factors and mechanisms that cause cancer cells to exclusively produce the M2 isoform.

By examining the levels of various splicing factors in numerous types of cancer cells, the scientists have narrowed the list of suspects to three proteins so far. All three are present at high levels in cancer cells, and repress the splicing of the harmless M1 isoform. This, by default, causes cells to produce only the M2 isoform.

The scientists could largely reverse this situation restoring M1 production while decreasing M2 levels and lactate production by forcing a reduction in the levels of the three splicing repressors. Whether this switch back to normal metabolism also impedes cancer cells' rapid growth remains to be tested.

"The cells didn't completely stop producing M2 when the three repressor proteins were blocked, which suggests that there might be other splicing factors that influence the switch between the two isoforms," explains Krainer. The team is now looking for these other potential splicing regulators.

"The field of cancer metabolism has reemerged, but several fundamental questions still remain about how the Warburg effect works," says Krainer. "We hope that our research on how alternative splicing regulates cellular
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Contact: Peter Tarr
tarr@cshl.edu
516-367-8455
Cold Spring Harbor Laboratory
Source:Eurekalert

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