title: Importance of glycolysis and oxidative phosphorylation in advanced melanoma.
abstract: Serum lactate dehydrogenase (LDH) is a prognostic factor for patients with stage IV melanoma. To gain insights into the biology underlying this prognostic factor, we analyzed total serum LDH, serum LDH isoenzymes, and serum lactate in up to 49 patients with metastatic melanoma. Our data demonstrate that high serum LDH is associated with a significant increase in LDH isoenzymes 3 and 4, and a decrease in LDH isoenzymes 1 and 2. Since LDH isoenzymes play a role in both glycolysis and oxidative phosphorylation (OXPHOS), we subsequently determined using tissue microarray (TMA) analysis that the levels of proteins associated with mitochondrial function, lactate metabolism, and regulators of glycolysis were all elevated in advanced melanomas compared with nevic melanocytes. To investigate whether in advanced melanoma, the glycolysis and OXPHOS pathways might be linked, we determined expression of the monocarboxylate transporters (MCT) 1 and 4. Analysis of a nevus-to-melanoma progression TMA revealed that MCT4, and to a lesser extend MCT1, were elevated with progression to advanced melanoma. Further analysis of human melanoma specimens using the Seahorse XF24 extracellular flux analyzer indicated that metastatic melanoma tumors derived a large fraction of energy from OXPHOS. Taken together, these findings suggest that in stage IV melanomas with normal serum LDH, glycolysis and OXPHOS may provide metabolic symbiosis within the same tumor, whereas in stage IV melanomas with high serum LDH glycolysis is the principle source of energy.
authors.affiliation: Department of Dermatology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Jonhan
authors.initials: J
authors.lastname: Ho
authors.forename: Michelle Barbi
authors.initials: MB
authors.lastname: de Moura
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Garret
authors.initials: G
authors.lastname: Vincent
authors.forename: Stephen
authors.initials: S
authors.lastname: Thorne
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Duncan
authors.forename: Lin
authors.initials: L
authors.lastname: Hui-Min
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Dorothea
authors.initials: D
authors.lastname: Becker
authors.forename: Bennett
authors.initials: B
authors.lastname: Van Houten
authors.forename: Stergios J
authors.initials: SJ
authors.lastname: Moschos
mesh_terms: D045744:Cell Line, Tumor; D018450:Disease Progression; D006019:Glycolysis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007527:Isoenzymes / Q000097:blood; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008545:Melanoma / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism; D009367:Neoplasm Staging; D009506:Nevus / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010086:Oxidative Phosphorylation Coupling Factors / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D027501:Monocarboxylic Acid Transporters; D010086:Oxidative Phosphorylation Coupling Factors; D007770:L-Lactate Dehydrogenase; C000628217:F(6) ATPase; D025261:Mitochondrial Proton-Translocating ATPases