Cancer cells tend to utilize aerobic glycolysis even under normoxic conditions, which is commonly called the “Warburg Effect.” Aerobic glycolysis often directly correlates with malignant potential. Though its purpose remains unclear, the “Warburg Effect” is thought to confer advantages to proliferation, survival and dissemination to cancer cells by increasing uptake of nutrients into biomass. KISS1 protein is secreted and proteolytically cleaved into kisspeptins (KP) that block the colonization of disseminated metastatic C8161.9 human melanoma cells at secondary sites. In this study, we hypothesized that KISS1 metastasis suppression occurs via regulation of aerobic glycolysis. Comparison of bioenergetic and metabolic aspects of glucose metabolism showed that all KISS1-secreting clones were less invasive, took up less glucose, produced less lactate which corresponds to higher pH[Ex], effects which were reversed when cells were transduced with shRNA to KISS1. The metabolism, invasion, and metastasis changes did not occur when KISS1 was missing the signal peptide (ΔSS). Utilizing a Seahorse bioanalyzer, KISS1, but not ΔSS cells showed significantly decreased extracellular acidification rates, increased O2 consumption and elevated mitochondria reserve capacity, an indicator of mitochondrial condition and a parameter thought to improve the cells’ ability to cope with oxidative stress. KISS1-expressing cells have 30-50% more mitochondria compared to vector or ΔSS-expressing cells. Increased mitochondrial mass was accompanied by significantly increased expression of mitochondrial genes involved in apoptosis and mitophagy, protein processing and trafficking. Increased mitochondrial mass correlated with higher PGC1α considered to be a master co-activator that regulates mitochondrial mass and metabolism. Interestingly, KISS1 differentially affects PGC1α-mediated downstream pathways, i.e. fatty acid synthesis and β-oxidation. KISS1-mediated up-regulation of mitochondria biogenesis appears to rely on KISS1 interaction with NRF1, a major transcription factor of mitochondria biogenesis. KP10 (which can activate the KISS1 receptor) does not alter pH[Ex] since the metastatic tumor cells do not express KISS1R. This paradox - metastasis and metabolic changes require secretion, but responding cells do not have the receptor - raises questions regarding the mechanism. Nonetheless, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism and metastasis. [Support: CA134581, Natl. Fndn. Cancer Res., Komen SAC110037].

Citation Format: Wen Liu, Benjamin H. Beck, Kedar S. Vaidya, Kevin T. Nash, Anne R. Diers, Kyle P. Feeley, Aimee Landar, Scott W. Ballinger, Danny R. Welch. The KISS1 metastasis suppressor appears to reverse the Warburg effect by enhancing mitochondria biogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3866. doi:10.1158/1538-7445.AM2013-3866