Boston-An ancient avenue for producing cellular energy, the glycolytic pathway, could provide a surprisingly rich target for anti-cancer therapies. A team of Harvard Medical School (HMS) researchers knocked down one of the pathway's enzymes, LDHA, in a variety of fast-growing breast cancer cells, effectively shutting down glycolysis, and implanted the cells in mice. Control animals carrying tumor cells with an intact glycolytic pathway did not survive beyond 10 weeks. In striking contrast, only two of the LDHA-deficient mice died, one at 16 weeks, another at just over 18 weeks. Eighty percent of the mice outlived the four month experiment. The findings by Valeria Fantin, Julie St-Pierre, and Philip Leder appear in the June Cancer Cell.
"This is an exciting contribution that reveals a surprising Achilles heel in cancer cells. It also adds to our sense of opportunity for new avenues of cancer therapeutics," said Stuart Schrieber, Morris Loeb professor and chair of the Department of Chemistry and Chemical Biology at Harvard University.
As a tumor grows, cells crowd one another and may be cut off from oxygen-carrying blood vessels--a distinct disadvantage since most cells require oxygen to produce the bulk of their energy-storing adenosine triphosphate (ATP). In the 1920s, Otto Warburg proposed that some cancer cells evolved the ability to switch over to an ancient, oxygen-free route, the glycolytic pathway. What is more, they continue to use this pathway even when access to oxygen is restored. Though the so-called Warburg effect has since been confirmed, the role played by glycolysis in cancer has been largely ignored. Few have attempted to attack specific points along the glycolytic pathway to gain a therapeutic effect.
"LDHA could be one weak point that we could attack but maybe, if we understand exactly all the steps involved, we could devise alternative strategies to attack the same pathway," said Fantin, who was an HM
Contact: Judith Montminy
Harvard Medical School