UCSF study shows suppression of telomerase enzyme can inhibit spread of melanoma
Mohammed Kashani-Sabet, M.D. -----
UCSF researchers have found that the spread of melanoma can be inhibited by suppressing telomerase, the enzyme active in cancer cell growth.
Findings reported in the July 5 Proceedings of the National Academy of Sciences show for the first time a link between telomerase and glycolysis, the metabolic pathway used to consume glucose and produce lactic acid within the body.
“Identification of this relationship has great significance in understanding the role of telomerase and glycolysis together,” said Mohammed Kashani-Sabet, MD, UCSF associate professor of dermatology and lead author of the study. “These results support the rationale for blocking telomerase in cancer therapy.”
In the study, researchers found through gene expression profiling in mice that eight genes involved in glucose metabolism were lowered when telomerase was suppressed in skin cancer cells. The result was a return of pigmentation, frequently absent in advanced melanomas, and of cancer cells losing their metastatic potential.
“We introduced a telomerase inhibitor into melanoma cells and found that by suppressing telomerase, melanoma cells start to change,” said Kashani-Sabet. “In some melanomas, pigmentation is lost. We found that when we are able to shut down telomerase, the cells regain functions previously lost, such as the ability to make pigment.”
“As the cells become too acidic from the buildup of lactic acid, the proteins that control pigment production can be turned off, suggesting that glucose metabolism plays a key role when combined with telomerase in metastasis.”
The ribonucleoprotein enzyme, telomerase, was discovered by study co-investigator Elizabeth Blackburn, PhD, Morris Herzstein Professor of Biology and Physiology in the UCSF Department of Biochemistry and Biophysics. Telomerase is well-documented as an instigator of cancer cell proliferation, but according to the researchers, its impact on tumor invasion and metastasis has been less studied.
In normal cells, the telomere is a strand of DNA that exists at the end of each chromosome and shortens with each cell division until it stops dividing, signaling the end of the cell life. Telomerase is activated in abnormal cells such as cancer cells, restoring the telomeres, and allowing them to divide and grow. As such, telomerase has been found to be over-expressed in 90 percent of human cancers.
Researchers were also able to ascertain for the first time how the use of a glucose compound injected into the body for positron emission topography (PET) scans was effective in diagnosing cancer. Use of the PET scan is now a regularly used method to diagnose and effectively pinpoint the source of cancer in an individual by utilizing radiation emitted from a patient to develop images. A radioactive substance is made up of glucose, a naturally occurring sugar, combined with a radioactive fluoride atom. The metabolism of glucose can be seen through gamma radiation produced from the positron-emitting fluoride that is detected by the PET scanner.
“Now for the first time, we understand why melanomas have high glucose uptake,” Kashani-Sabet said. “We knew that use of PET scanning was effective in detecting melanoma metastasis, but we really didn’t know why. Through this study, we found that telomerase is responsible for activation of glycolysis in melanoma cells.”
Connecting telomerase and glucose metabolism together has implications for further therapeutic study. “By manipulating telomerase in cancer cells and suppressing glycolysis, it is possible to inhibit both melanoma invasion and metastasis.”
The study was funded by the Zackheim Endowment Fund, American Cancer Society, Damon Runyon Postdoctoral Fellowship program, Steven and Michelle Kirsch Foundation and the U.S. Public Health Service grants.
Co-authors from UCSF were Sepideh Bagheri and Mehdi Nosrati, Comprehensive Cancer Center and Department of Dermatology; Shang Li and Elizabeth H. Blackburn, Department of Biochemistry and Biophysics; Sima Torabian, Javier Rangel, and Dan H. Moore, Department of Epidemiology and Biostatistics; Scot Federman, Rebecca R. LaPosa, Frederick L. Baehner, Richard W. Sagebiel, James E. Cleaver, and Christopher Haqq, Department of Medicine and Comprehensive Cancer Center. Co-authors from California Pacific Medical Research Institute, San Francisco, were Sylvia Fong and Robert J. Debs.
UCSF is a leading university that consistently defines health care worldwide by conducting advanced biomedical research, educating graduate students in the life sciences, and providing complex patient care.
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