Melatonin Reverses the Warburg-Type Metabolism and Reduces Mitochondrial Membrane Potential of Ovarian Cancer Cells Independent of MT1 Receptor Activation
Maira Smaniotto Cucielo,
Roberta Carvalho Cesário,
Henrique Spaulonci Silveira,
Letícia Barbosa Gaiotte,
Sérgio Alexandre Alcantara dos Santos,
Debora Aparecida Pires de Campos Zuccari,
Fábio Rodrigues Ferreira Seiva,
Russel J. Reiter,
Luiz Gustavo de Almeida Chuffa
Affiliations
Maira Smaniotto Cucielo
Department of Structural and Functional Biology, Institute of Biosciences, UNESP—São Paulo State University, Botucatu 18618-689, São Paulo, Brazil
Roberta Carvalho Cesário
Department of Structural and Functional Biology, Institute of Biosciences, UNESP—São Paulo State University, Botucatu 18618-689, São Paulo, Brazil
Henrique Spaulonci Silveira
Department of Structural and Functional Biology, Institute of Biosciences, UNESP—São Paulo State University, Botucatu 18618-689, São Paulo, Brazil
Letícia Barbosa Gaiotte
Department of Structural and Functional Biology, Institute of Biosciences, UNESP—São Paulo State University, Botucatu 18618-689, São Paulo, Brazil
Sérgio Alexandre Alcantara dos Santos
Department of Structural and Functional Biology, Institute of Biosciences, UNESP—São Paulo State University, Botucatu 18618-689, São Paulo, Brazil
Debora Aparecida Pires de Campos Zuccari
Cancer Molecular Research Laboratory (LIMC), FAMERP, Department of Molecular Biology, São José do Rio Preto 15090-000, São Paulo, Brazil
Fábio Rodrigues Ferreira Seiva
Biological Science Center, Department of Biology, Luiz Meneghel Campus, Universidade Estadual do Norte do Paraná—UENP, Bandeirantes 86360-000, Paraná, Brazil
Russel J. Reiter
Department of Cell Systems and Anatomy, UT Health, San Antonio, TX 78229, USA
Luiz Gustavo de Almeida Chuffa
Department of Structural and Functional Biology, Institute of Biosciences, UNESP—São Paulo State University, Botucatu 18618-689, São Paulo, Brazil
Ovarian cancer (OC) is the most lethal gynecologic malignancy, and melatonin has shown various antitumor properties. Herein, we investigated the influence of melatonin therapy on energy metabolism and mitochondrial integrity in SKOV-3 cells and tested whether its effects depended on MT1 receptor activation. SKOV-3 cells were exposed to different melatonin concentrations, and experimental groups were divided as to the presence of MT1 receptors (melatonin groups) or receptor absence by RNAi silencing (siRNA MT1+melatonin). Intracellular melatonin levels increased after treatment with melatonin independent of the MT1. The mitochondrial membrane potential of SKOV-3 cells decreased in the group treated with the highest melatonin concentration. Melatonin reduced cellular glucose consumption, while MT1 knockdown increased its consumption. Interconversion of lactate to pyruvate increased after treatment with melatonin and was remarkable in siRNA MT1 groups. Moreover, lactate dehydrogenase activity decreased with melatonin and increased after MT1 silencing at all concentrations. The UCSC XenaBrowser tool showed a positive correlation between the human ASMTL gene and the ATP synthase genes, succinate dehydrogenase gene (SDHD), and pyruvate dehydrogenase genes (PDHA and PDHB). We conclude that melatonin changes the glycolytic phenotype and mitochondrial integrity of SKOV-3 cells independent of the MT1 receptor, thus decreasing the survival advantage of OC cells.
