Abstract 126: The KISS1 metastasis suppressor appears to integrate glycolysis, mitochondrial biogenesis and metastasis via regulation of a PGC1α pathway

Abstract

Abstract Considering the enormous energy requirements and stresses of the metastatic cascade, an interrelationship with aerobic glycolysis seems intuitive, but has not been definitively established. The purpose of these studies was to determine whether there is a relationship between KISS1 metastasis suppression and metabolism. Wild-type KISS1 expressed in human melanoma cells were metastasis suppressed and took up less glucose and produced less lactate, corresponding to higher pH[Ex]. Metabolism and metastasis changes did not occur when KISS1 was missing the secretion signal peptide (ΔSS). Changes in glucose transport and key glycolytic enzymes did not consistently correlate with metabolic changes; however, V-ATPase, which promotes extracellular acidification, invasion and metastasis, appears to be involved in KISS1-mediated metabolic changes. Also corresponding with the shift from glycolysis to oxidative phosphorylation, KISS1-expressing cells have 30-50% more mitochondrial mass accompanied increased higher expression of PPARγ co-activator 1α (PGC1α), a master regulator of mitochondrial biogenesis. PGC1α-mediated downstream pathways (i.e. fatty acid synthesis and β-oxidation) are differentially regulated by KISS1, apparently reliant upon direct KISS1 interaction with Nuclear Respiratory Factor 1 (NRF1), a major transcription factor involved in mitochondrial biogenesis. KISS1 does not affect PGC1α mRNA expression but stabilizes the protein through interaction with the ubiquitin-like protein, UBQLN1. To test whether a KISS1- PGC1α axis is critical for metastasis suppressor function, shRNA to KISS1 or PGC1α was introduced into KISS1-expressing cells. Metabolic changes and suppression of invasion and migration were reversed. Importantly, knock-down of PGC1α abolished KISS1-mediated metastasis suppression in vivo, strongly suggesting that PGC1α is an essential downstream mediator of KISS1 as a metastasis suppressor. Taken together, these data define a novel signaling pathway controlling metabolism and metastasis. Moreover, these data appear to directly connect changes in aerobic glycolysis, mitochondrial metabolism, and cancer metastasis. Citation Format: Wen Liu, Benjamin Beck, Kedar S. Vaidya, Kevin T. Nash, Scott W. Ballinger, Danny R. Welch. The KISS1 metastasis suppressor appears to integrate glycolysis, mitochondrial biogenesis and metastasis via regulation of a PGC1α pathway. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 126. doi:10.1158/1538-7445.AM2014-126