Tumor and Stem Cell Biology MetastasisSuppressorKISS1Seems toReverse theWarburg Effect by Enhancing Mitochondrial Biogenesis

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 (DSS), invasion and metastasis are no longer suppressed and cells continue to metabolize using aerobic glycolysis. KISS1-expressing cells have 30% to 50% more mitochondrial mass than DSS-expressing cells, which are accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1a, a master coactivator that regulates mitochondrial mass and metabolism. PGC1a-mediated downstream pathways (i.e., fatty acid synthesis and b-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction withNRF1, amajor transcription factor involved inmitochondrial biogenesis. Since the downstream effects could be reversed using short hairpin RNA to KISS1 or PGC1a, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism, and metastasis. Cancer Res; 74(3); 954–63. 2013 AACR.