Researchers attack tumor cells by exploiting dependency on sugar metabolismAlthough scientists have known for nearly 90 years that cancer cells commonly display altered sugar metabolism, the molecular significance of this phenomenon is not completely understood. Now, a new study published in the June issue of Cancer Cell reveals a functional connection between carbohydrate-driven energy production and tumor maintenance. Importantly, the results suggest that inhibition of a specific aspect of glucose metabolism may represent an attractive and potentially well-tolerated approach to interfering with tumor growth.
Normal cells produce most of the ATP they need to power cellular functions through an oxygen-dependent process known as oxidative phosphorylation. In contrast, cancer cells commonly switch to what is known as a "glycolytic phenotype," producing ATP through a process that can occur in the absence of oxygen and involves conversion of glucose to lactate. Scientists believe that the glycolytic phenotype enables rapidly proliferating tumor cells to survive even when environmental oxygen levels are not optimal. In addition, perturbations of the normal physiology of mitochondria, cellular structures involved in oxygen-dependent ATP production, have also been linked to cancer.
Dr. Valeria Fantin, formerly of the Department of Genetics at Harvard Medical School, and colleagues examined whether blocking the conversion of glucose to lactate in mammary tumor cells might help shed light on the association between tumor survival and the interplay between glycolytic phenotype and mitochondrial metabolism. The researchers used a sophisticated genetic technique to reduce levels of lactate dehydrogenase A (LDH-A), an enzyme required for the glucose to lactate pathway that is elevated in human breast and lung cancers. Inhibition of LDH-A stimulated mitochondrial function and drastically compromised the ability of the tumor cells to proliferate in low oxygen conditions. Restoration of LDH-A activity reestablished the glycolytic phenotype of the tumor cells.
These data suggest that alterations in glucose metabolism in cancer cells are linked with changes in mitochondrial physiology and that LDH-A plays a critical role in tumor growth. The researchers propose that inhibition of LDH-A may represent a rational and safe strategy for treatment of cancer. "Because individuals with complete hereditary deficiency of LDH-A do not show any symptoms under ordinary circumstances, the genetic data suggest that inhibition of LDH-A activity may represent a relatively nontoxic approach to interfere with tumor growth," explains Dr. Fantin.
The researchers include Valeria R. Fantin of Harvard Medical School and Howard Hughes Medical Institute in Boston, MA and Merck & Co., Inc. in Boston, MA; Julie St-Pierre of Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA and Institut de Recherche en Immunologie et en Cancérologie (IRIC), Université de Montréal Pavillon Marcelle-Coutu in Montréal, Québec, Canada; Philip Lederof Harvard Medical School and Howard Hughes Medical Institute in Boston, MA.
Fantin et al.: "Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance."
Publishing in Cancer Cell 9, 425–434, June 2006. DOI 10.1016/j.ccr.2006.04.023 www.cancercell.org
Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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