Open Access Highly Accessed Research

Importance of glycolysis and oxidative phosphorylation in advanced melanoma

Jonhan Ho1, Michelle Barbi de Moura2, Yan Lin3, Garret Vincent4, Stephen Thorne5, Lyn M Duncan6, Lin Hui-Min3, John M Kirkwood4, Dorothea Becker7, Bennett Van Houten2 and Stergios J Moschos48*

Author Affiliations

1 Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

2 Departments of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

3 Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, 15213, USA

4 Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA

5 Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA

6 Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA

7 Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15213, USA

8 Present Address: Clinical Associate Professor, Department of Medicine, University of North Carolina at Chapel Hill Physicians Office Building, 3rd Floor, Suite 3116, CB #7305, 170 Manning Drive, Chapel Hill, NC, 27599, USA

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Molecular Cancer 2012, 11:76  doi:10.1186/1476-4598-11-76

Published: 9 October 2012

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.

Keywords:
Melanoma; Lactate dehydrogenase; Glycolysis; Mitochondria; Oxidative phosphorylation; Monocarboxylate transporters