Glutamine plays an important role in cellular growth in several cancers. A Rice University-led study shows how ovarian cancer metabolism changes between early and late stages. In this study, a further link between glutamine dependency and tumor invasiveness is established in ovarian cancer.
A Rice University-led analysis of the metabolic profiles of hundreds of ovarian tumors has revealed a new test to determine whether ovarian cancer cells have the potential to metastasize, or spread to other parts of the body. The study also suggests how ovarian cancer treatments can be tailored based on the metabolic profile of a particular tumor.
The research, which appears online this week in Molecular Systems Biology, was conducted at the Texas Medical Center in Houston by researchers from Rice University, the University of Texas M.D. Anderson Cancer Center, and the Baylor College of Medicine.
“We found a striking difference between the metabolic profiles of poorly aggressive and highly aggressive ovarian tumor cells, particularly with respect to their production and use of the amino acid glutamine,” said lead researcher Deepak Nagrath Ph.D. of Rice University. “For example, we found that highly aggressive ovarian cancer cells are glutamine-dependent, and in our laboratory studies, we showed that depriving such cells of external sources of glutamine — as some experimental drugs do — was an effective way to kill late-stage cells.
“The story for poorly aggressive cells was quite different,” said Nagrath, Assistant Professor of Chemical and Biomolecular Engineering at Rice. “These cells use an internal metabolic pathway to produce a significant portion of the glutamine that they consume, so a different type of treatment — one aimed toward internal glutamine sources — will be needed to target cells of this type.”
The research is part of a growing effort among cancer researchers worldwide to create treatments that target the altered metabolism of cancer cells. It has long been known that cancer cells adjust their metabolism in subtle ways that allow them to proliferate faster and survive better. In 1924, Otto Warburg showed that cancer cells produced far more energy from glycolysis than did normal cells. The Nobel Prize-winning discovery became known as the “Warburg effect,” and researchers long believed that all cancers behaved in this way. Intense research in recent decades has revealed a more nuanced picture.
“Each type of cancer appears to have its own metabolic signature,” Nagrath said. “For instance, kidney cancer does not rely on glutamine, and though breast cancer gets some of its energy from glutamine, it gets even more from glycolysis. For other cancers, including glioblastoma and pancreatic cancer, glutamine appears to be the primary energy source.”
Nagrath, director of Rice University’s Laboratory for Systems Biology of Human Diseases, said the new metabolic analysis indicates that ovarian cancer may be susceptible to multidrug cocktails, particularly if the amounts of the drugs can be tailored to match the metabolic profile of a patient’s tumor.
The research also revealed a specific biochemical test that pathologists could use to guide such treatments. The test involves measuring the ratio between the amount of glutamine that a cell takes up from outside and the amount of glutamine it makes internally.
“This ratio proved to be a robust marker for prognosis,” said University of Texas M.D. Anderson Cancer Center co-author Anil Sood, M.D., Professor of Gynecologic Oncology and Reproductive Medicine and co-director of the Center for RNA Interference and Non-Coding RNA. “A high ratio was directly correlated to tumor aggression and metastatic capability. Patients with this profile had the worst prognosis for survival.”
The three-year study included cell culture studies at Rice as well as a detailed analysis of gene-expression profiles of more than 500 patients from the Cancer Genome Atlas and protein-expression profiles from about 200 M.D. Anderson patients.
“The enzyme glutaminase is key to glutamine uptake from outside the cell, and glutaminase is the primary target that everybody is thinking about right now in developing drugs,” Nagrath said. “We found that targeting only glutaminase will miss the less aggressive ovarian cancer cells because they are at a metabolic stage where they are not yet glutamine-dependent.”
Rice University graduate student Lifeng Yang, lead author of the study, designed a preclinical experiment to test the feasibility of a multidrug approach, involving the use of a JAK inhibitor and a glutaminase inhibitor. This “drug cocktail” approach inhibited the early stage production of internal glutamine, while also limiting the uptake of external glutamine.
“That depleted all sources of glutamine for the cells, and we found that cell proliferation decreased significantly,” Yang said.
Nagrath said the study also revealed another key finding — a direct relationship between glutamine and an ovarian cancer biomarker called “STAT3” (Signal Transducer And Activator Of Transcription 3).
“A systems-level understanding of the interactions between metabolism and signaling is vital to developing novel strategies to tackle cancer,” said M.D. Anderson co-author Prahlad Ram Ph.D., Associate Professor of Systems Biology and co-director of the M.D. Anderson Cancer Center’s Systems Biology Program. “STAT3 is the primary marker that is used today to ascertain malignancy, tumor aggression and metastasis in ovarian cancer.”
Nagrath said, “The higher STAT3 is, the more aggressive the cancer. For the first time, we were able to show how glutamine regulates STAT3 expression through a well-known metabolic pathway called the TCA cycle, which is also known as the ‘Krebs cycle.’”
Nagrath said the research is ongoing. Ultimately, Dr. Nagrath hopes the investigations will lead to new treatment regimens for cancer as well as a better understanding of the role of cancer-cell metabolism in metastasis and drug resistance.
Co-authors include Hongyun Zhao, Stephen Wahlig, Abhinav Achreja and Julia Win (all affiliated with Rice University); Tyler Moss, Lingegowda Mangala, Guillermo Armaiz-Pena, Dahai Jiang, Rajesha Roopaimoole, Cristian Rodriguez-Aguayo, Imelda Mercado-Uribe, Gabriel Lopez-Berestein and Jinsong Liu (all affiliated with M.D. Anderson Cancer Center); Juan Marini of Baylor College of Medicine; and Takashi Tsukamoto of Johns Hopkins University.
The research was supported by seed funding from (i) the Collaborative Advances in Biomedical Computing Program at Rice Univesity’s Ken Kennedy Institute for Information Technology, (ii) Rice University’s John and Ann Doerr Fund for Computational Biomedicine, (iii) the Odyssey Fellowship Program at the MD Anderson Cancer Center, (iv) the estate of C.G. Johnson Jr., (v) the National Institutes of Health, (vi) the Cancer Prevention and Research Institute of Texas, (v) the Ovarian Cancer Research Fund, (vi) the Blanton-Davis Ovarian Cancer Research Program, (vii) the Gilder Foundation, and (viii) the MD Anderson Cancer Center.
- “Glutamine ratio is key ovarian cancer indicator,” by Jade Boyd, Press Release, Rice University, May 5, 2014.
- Yang L, et. al. “Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer.” Mol Syst Biol. (2014) 10: 728. DOI: 10.1002/msb.20134892, published May 5, 2014.