Importance of glycolysis and oxidative phosphorylation in advanced melanoma.

Jonhan Ho,Dorothea Becker,Stergios J Moschos,Yan Lin,Lyn M Duncan,Lin Hui-Min,Garret Vincent,Bennett Van Houten,John M Kirkwood,Michelle Barbi De Moura,Stephen Thorne

doi:10.1186/1476-4598-11-76

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.

Highlights

It is widely accepted that metabolic changes are one of the hallmarks of cancer [1]
Analysis of serum lactate dehydrogenase (LDH) isoenzymes in metastatic melanomas Of the five tetrameric LDH isoenzymes, LDH1 and LDH2 are preferentially associated with conversion of pyruvate from lactate for use in oxidative phosphorylation (OXPHOS), while LDH4 and LDH5 are involved in the production of lactate in glycolysis (Additional file 1) [23]
To assess whether any of the serum LDH isoenzymes or serum lactate correlated with overall survival (OS) we performed a survival analysis

Summary

Introduction

It is widely accepted that metabolic changes are one of the hallmarks of cancer [1]. Within the three-dimensional tumor where blood supply, and oxygenation, can be variable, it has been proposed that its center, which is less oxygenated, is predominantly dependent on glycolysis, whereas the more vascularized tumor periphery is more dependent on OXPHOS These two spatially distinct populations can be metabolically linked such that lactate from the glycolytic portion of the tumor helps fuel ATP production in the vascularized region of the tumor through OXPHOS in a process termed metabolic symbiosis [9,10]. It is presently not known whether metastatic melanomas utilize these two crucial metabolic pathways in concert or sequentially

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Results

Conclusion