title: Metastasis suppressor KISS1 seems to reverse the Warburg effect by enhancing mitochondrial biogenesis.
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 (ΔSS), 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 ΔSS-expressing cells, which are accompanied by correspondingly increased mitochondrial gene expression and higher expression of PGC1α, a master coactivator that regulates mitochondrial mass and metabolism. PGC1α-mediated downstream pathways (i.e., fatty acid synthesis and β-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 short hairpin RNA to KISS1 or PGC1α, these data appear to directly connect changes in mitochondria mass, cellular glucose metabolism, and metastasis.
authors.affiliation: Authors' Affiliations: Department of Cancer Biology; The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, Kansas; and Department of Pathology, University of Alabama-Birmingham, Birmingham, Alabama.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Beck
authors.forename: Kedar S
authors.initials: KS
authors.lastname: Vaidya
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Nash
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Feeley
authors.forename: Scott W
authors.initials: SW
authors.lastname: Ballinger
authors.forename: Keke M
authors.initials: KM
authors.lastname: Pounds
authors.forename: Warren L
authors.initials: WL
authors.lastname: Denning
authors.forename: Anne R
authors.initials: AR
authors.lastname: Diers
authors.forename: Aimee
authors.initials: A
authors.lastname: Landar
authors.forename: Animesh
authors.initials: A
authors.lastname: Dhar
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
authors.forename: Danny R
authors.initials: DR
authors.lastname: Welch
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D059648:Kisspeptins / Q000235:genetics* / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C106628:KISS1 protein, human; D059648:Kisspeptins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D019344:Lactic Acid; D005947:Glucose