- Growing tumors often have areas of low oxygen, a condition called hypoxia.
- How cancer cells survive and thrive under the stress of hypoxia is poorly understood.
- This study shows how cancer cells change their use of the amino acid glutamine first as an energy source, then to produce lipids that are needed for cell proliferation.
The study focuses on how cancer cells use the amino acid 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.
The findings were published in the journal Cell Metabolism.
“These results are particularly exciting because glutamine metabolism is a potential target for anticancer therapy,” says principal investigator Nicholas Denko, PhD, MD, associate professor of radiation oncology at the OSUCCC – James.
“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.
“We show that we can block the growth of model tumors by redirecting hypoxic glutamine metabolism to make it follow the normal-oxygen pathway. 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,” says Denko, who is a member of the OSUCCC – James Molecular Biology and Cancer Genetics Program.
Denko and first author Ramon C. Sun, a postdoctoral researcher in radiation oncology, used several tumor-cell lines and an animal model for this study. Their key findings include:
Hypoxia activates HIF1, leading to the breakdown of the enzyme called OGDH2, which is necessary for the typical use of glutamine to produce energy via the tricarboxylic acid, or Krebs cycle.
When OGDH2 is lost, hypoxic cancer cells divert glutamine away from energy production and use it to generate citrate that is then used to produce the lipids needed for cell proliferation.
Tumors with malignant cells that are forced to express a hypoxia-resistant form of OGDH2 grew significantly slower in an animal model than tumors with normal OGDH2, suggesting that reversing this hypoxic pathway might be an effective strategy for inhibiting tumor growth.
Funding from the NIH/National Cancer Institute (grant P01 CA67166) supported this research.
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State’s cancer program as “exceptional,” the highest rating given by NCI survey teams. As the cancer program’s 228-bed adult patient-care component, The James is a “Top Hospital” as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.
A high quality JPEG of Nicholas Denko, MD, PhD, is available here.
Contact: Darrell E. Ward, Wexner Medical Center Public Affairs and Media Relations, at 614-293-3737, or [email protected]