Targeting Tumor Metabolism with Next-Generation Drugs
Scientists in Ohio identified the molecular pathway that allows cancer cells to grow in hypoxic areas of a tumor. The team believes their findings might provide a novel strategy for inhibiting tumor growth by developing drugs that reverse this hypoxia-related pathway.
The study, which was carried out at the Ohio State University Comprehensive Cancer Center, looked at how cancer cells use glutamine, the most common amino acid found free in the bloodstream. Under normal oxygen levels, healthy cells use glutamine largely to produce energy, with a small amount diverted to make fatty acids and lipids.
But when oxygen levels drop in areas of a growing tumor, the hypoxic conditions activate a gene called HIF1, initiating a pathway that shifts the use of glutamine away from energy production and to the synthesis of lipids needed for cell proliferation.
“We now identify the mechanism by which HIF1 activation results in a dramatic reduction in the activity of the key mitochondrial enzyme complex α ketoglutarate dehydrogenase (αKGDH),” wrote the investigators in their study, “Hypoxic Regulation of Glutamine Metabolism through HIF1 and SIAH2 Supports Lipid Synthesis that Is Necessary for Tumor Growth, which is published in Cell Metabolism. “HIF1 activation promotes SIAH2-targeted ubiquitination and proteolysis of the 48 kDa splice variant of the E1 subunit of the αKGDH complex (OGDH2).”
“These results are particularly exciting because glutamine metabolism is a potential target for anticancer therapy,” says principal investigator Nicholas Denko, M.D., Ph.D., associate professor of radiation oncology at the cancer center.
“Tumor cells require glutamine to grow, so groups have been trying to identify drugs that block glutamine metabolism and inhibit tumor growth. However, drugs that completely block glutamine metabolism will have unwanted side effects because glutamine is also an important neurotransmitter,” he says.
As a result, the team came up with a promising approach.
“Knockdown of SIAH2 or mutation of the ubiquitinated lysine residue on OGDH2 (336KA) reverses the hypoxic drop in αKGDH activity, stimulates glutamine oxidation, and reduces glutamine-dependent lipid synthesis,” they explained in their journal article. “336KA OGDH2-expressing cells require exogenous lipids or citrate for growth in hypoxia in vitro and fail to grow as model tumors in immunodeficient mice. Reversal of hypoxic mitochondrial function may provide a target for the development of next-generation anticancer agents targeting tumor metabolism.”
“We show that we can block the growth of model tumors by redirecting hypoxic glutamine metabolism to make it follow the normal-oxygen pathway,” adds Dr. Denko. “Such a therapeutic strategy should have few, if any, unwanted side effects, because normal tissue is oxygenated and already using glutamine in the normal manner.”