Submitted to: Cancer Research
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/6/2013
Publication Date: 2/1/2014
Citation: Liu, W., Beck, B.H., Vaidya, K.S., Nash, K.T., Feeley, K.P., Ballinger, S.W., Pounds, K.M., Denning, W.L., Diers, A.R., Landar, A., Dhar, A., Iwakuma, T., Welch, D.R. 2014. Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis. Cancer Research. 74(3):954-963. Interpretive Summary: The most lethal aspect of cancer is metastasis, which is the process by which a cancer cells spread from primary sites to distant sites throughout the body. In melanoma (a type of skin cancer) patients, five-year survival can be quite high (approximately 98%) if the tumor cells are confined to a primary site on the skin; however, if the melanoma cells spread to other sites such as the lung, 5-year survival estimates drop to 16%. Clearly, new therapies are desperately needed for patients suffering from metastatic melanoma. One potential therapeutic target is the KISS1 metastasis suppressor. KISS1 is a gene that has been shown to prevent the spread of melanoma, breast and ovarian cancers in animal models. Therefore, in this study we sought to better understand how KISS1 prevents the spread of cancer. We focused our efforts on understanding how regular melanoma cells (that do not have a normal copy of the KISS1 gene), and those engineered to express KISS1, obtain the energy they need to survive and proliferate. We found that regular melanoma cells used an inefficient energy yielding pathway called glycolysis, while melanoma cells that have the KISS1 gene used oxygen as a source to yield energy, much like a normal cell of the skin. We found that this key difference was driven by a certain gene called PGC1 alpha. These findings highlight how KISS1 is working in melanoma cells, and may represent a potential treatment for melanoma.
Technical Abstract: Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, commonly called the "Warburg Effect." Aerobic glycolysis often directly correlates with malignancy, but its purpose, if any, in metastasis remains unclear. When wild-type KISS1 metastasis suppressor is expressed, aerobic glycolysis decreases and oxidative phosphorylation predominates. However, when KISS1 is missing the secretion signal peptide (delta SS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30-50% more mitochondrial mass than delta SS-expressing cells, which is accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1 alpha, a master co-activator that regulates mitochondrial mass and metabolism. PGC1 alpha-mediated downstream pathways (i.e. fatty acid synthesis and beta-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with NRF1, a major transcription factor involved in mitochondrial biogenesis. Since the downstream effects could be reversed using shRNA to KISS1 or PGC1 alpha, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism and metastasis.