Journal Article

Serotonin activates glycolysis and mitochondria biogenesis in human breast cancer cells through activation of the Jak1/STAT3/ERK1/2 and adenylate cyclase/PKA, respectively

Figueiredo, Claudia P., Paixão, Larissa P., Branco, Jessica R., Albanese, Jamille M., Zancan, Patricia, Ochioni, Alan C., Sola-Penna, Mauro, Baptista-de-Souza, Daniela, Coelho, Wagner S., Marcondes, Mariah C., Mundim, Davi M.

2020

Overview

Background Although produced by several types of tumours, the role of serotonin on cancer biology is yet to be understood. Methods The effects of serotonin (5-HT) on human breast cancer cells proliferation, signalling pathways and metabolic profile were evaluated by cytometry, western blotting, qPCR, enzymology and confocal microscopy. Results Our results revealed that incubation of MCF-7 cells with 10 µM 5-HT increased cell growth rate by 28%, an effect that was prevented by the 5-HTR 2A/C antagonist, ketanserin. Conversely, increasing concentrations of 5-HT promoted glucose consumption and lactate production by MCF-7 cells. We also showed that increased glucose metabolism is provoked by the upregulation of pyruvate kinase M2 (PKM2) isoform through 5-HTR 2A/C -triggered activation of Jak1/STAT3 and ERK1/2 subcellular pathways. However, we noticed a decrease in the rate of produced lactate per consumed glucose as a function of the hormone concentration, suggesting a disruption of the Warburg effect. The latter effect is due to 5-HTR 2A/C -dependent mitochondrial biogenesis and metabolism, which is triggered by adenylyl cyclase/PKA, enhancing the oxidation of lactate within these cells. Conclusions We showed that serotonin, through 5-HTR 2A/C , interferes with breast cancer cells proliferation and metabolism by triggering two distinct signalling pathways: Jak1/STAT3 that boosts glycolysis through upregulation of PKM2, and adenylyl cyclase/PKA that enhances mitochondrial biogenesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1347 / 631/80/304 / Adenylate cyclase / Adenylyl Cyclases - genetics / Apoptosis - drug effects / Biomedical and Life Sciences / Biomedicine / Biosynthesis / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Cancer Research / Carrier Proteins - genetics / Cell activation / Cell proliferation / Cell Proliferation - drug effects / Cell Survival - drug effects / Confocal microscopy / Cytometry / Drug Resistance / Epidemiology / Extracellular signal-regulated kinase / Female / Glucose - metabolism / Glycolysis / Glycolysis - drug effects / Growth rate / Humans / Janus kinase / Janus Kinase 1 - genetics / Ketanserin / Ketanserin - pharmacology / Lactic acid / MAP Kinase Signaling System - genetics / MCF-7 Cells / Membrane Proteins - genetics / Metabolism / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Molecular Medicine / Oncology / Oxidation / Protein kinase A / Pyruvate kinase / Pyruvic acid / Serotonin / Serotonin - pharmacology / Signal transduction / Stat3 protein / STAT3 Transcription Factor - genetics / Thyroid Hormone-Binding Proteins / Thyroid Hormones - genetics / Tumors / Western blotting