Melatonin Cytotoxicity Is Associated to Warburg Effect Inhibition in Ewing Sarcoma Cells.

Ana M Sanchez-Sanchez,Santos Suarez,Vanesa Martin,Carmen Rodriguez,Noelia Puente-Moncada,Marina Gomez-Lobo,Isaac Antolin,David M Loeb

doi:10.1371/journal.pone.0135420

Abstract

Melatonin kills or inhibits the proliferation of different cancer cell types, and this is associated with an increase or a decrease in reactive oxygen species, respectively. Intracellular oxidants originate mainly from oxidative metabolism, and cancer cells frequently show alterations in this metabolic pathway, such as the Warburg effect (aerobic glycolysis). Thus, we hypothesized that melatonin could also regulate differentially oxidative metabolism in cells where it is cytotoxic (Ewing sarcoma cells) and in cells where it inhibits proliferation (chondrosarcoma cells). Ewing sarcoma cells but not chondrosarcoma cells showed a metabolic profile consistent with aerobic glycolysis, i.e. increased glucose uptake, LDH activity, lactate production and HIF-1α activation. Melatonin reversed Ewing sarcoma metabolic profile and this effect was associated with its cytotoxicity. The differential regulation of metabolism by melatonin could explain why the hormone is harmless for a wide spectrum of normal and only a few tumoral cells, while it kills specific tumor cell types.

Highlights

Ewing sarcoma is the second most frequent primary bone tumor after osteosarcoma, accounting for 10–15% of these pathologies
Most cancer cells frequently display a metabolic profile different to normal cells. They have higher rates of cytosolic glycolysis, uptaking more glucose and producing an excess of lactic acid [18,21]. We evaluated these parameters characteristic of the tumoral Warburg effect in two sarcoma cell lines: sw-1353 chondrosarcoma cells and TC-71 Ewing sarcoma cells
All results together show an evident difference in basal energy metabolism between chondrosarcoma and Ewing sarcoma cells, which in turn may be related to the differential effect of melatonin on both cell types

Summary

Introduction

Ewing sarcoma is the second most frequent primary bone tumor after osteosarcoma, accounting for 10–15% of these pathologies. It primarily affects children and young adults, with a peak incidence in the second decade of life. A combination of chemotherapy, surgery and radiation therapy results in 65% of patients free of disease after 4 years in those without metastases at diagnosis. Antitumoral effects of melatonin have been extensively described in a wide variety of tumor cell types. This indolamine inhibits proliferation in the majority of tumor cells through several possible intracellular signaling pathways [2] including antioxidant actions [3,4,5]. Melatonin is able to kill some specific tumor types, such as Ewing sarcoma or hematological

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Conclusion