Tumors' alternative energy source could become a new target for anti-melanoma therapy
INDIANAPOLIS – Melanoma tumors switch to an alternative energy system when they develop resistance to chemotherapy, making that alternative system an attractive target for new treatments, according to researchers at Indiana University School of Medicine.
Malignant melanoma is one of the most lethal forms of cancer, responsible for 95 percent of skin cancer-related deaths. When the cancer has not spread, surgery is an effective treatment option. If it has spread, drugs that block the activity of the mutated gene successfully shrink the tumors, but the tumors eventually develop resistance to the drugs, leaving physicians without effective treatment options.
The research, recently published in the Journal of Biological Chemistry, focused on the subtype of malignant melanoma that contains a particular genetic mutation found in nearly 50 percent of such tumors.
Like most cells in the body, cancer cells process glucose to provide the energy needed for cellular activities and proliferation. However, previous research with PET scans has shown that glucose levels drop significantly in melanoma tumor cells as they develop resistance to drugs.
In the new study, researchers led by Samisubbu R. Naidu, PhD, research assistant professor of microbiology and immunology, determined that more than half of malignant melanomas, those carrying the mutant gene, shifted from using glucose to acetate as a main source of energy. The researchers also identified the enzyme responsible for conversion of acetate into energy.
These findings highlight the potential of this enzyme as a novel target for a new anti-melanoma therapy, Dr. Naidu said.
"If we can develop a drug that can effectively inhibit this enzyme, we could extend the life of melanoma patients from months to years," he said.
The study focused on melanoma cells containing a mutant BRAF protein, which directs the cells to proliferate and survive in nutrient-limited environments.
In a series of experiments, the researchers grew melanoma cells in various combinations of nutritional media and found that supplementing the media with acetate enabled the cells to survive and proliferate in the absence of glucose.
Subsequently, it was found that in the absence of glucose, mitochondria, the cellular organelles commonly known as the “powerhouse of the cell,” were increasingly active in the energy production, using acetate as a fuel. One particular enzyme enabled the use of this alternative source of energy. Importantly, by deleting this gene in melanoma cells, the authors showed that melanoma tumor growth in mice was blunted.
Dr. Naidu noted that mutations in the BRAF gene are found in many other types of cancer. Therefore, he said, "The benefits of this discovery may well go beyond melanoma."
Financial support for this research was provided in part by the Indiana Clinical and Translational Sciences Institute Independent Scientist Award, Indiana CTSI Core awards, the Ralph W. and Grace M. Showalter Research Trust as well as funds from Hal E. Broxmeyer, PhD, Distinguished Professor and professor of microbiology and immunology.
In addition to Dr. Naidu and Dr. Broxmeyer, investigators contributing to the work were Alexander J. Lakhter, James Hamilton, Raymond L Konger and Nickolay Brustovetsky, all of IU School of Medicine.
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