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

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

doi:10.1038/s41416-019-0640-1

Mauro Sola-Penna, Mariah C Marcondes + Show 9 more

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https://doi.org/10.1038/s41416-019-0640-1

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BackgroundAlthough produced by several types of tumours, the role of serotonin on cancer biology is yet to be understood.MethodsThe 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.ResultsOur 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-HTR2A/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-HTR2A/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-HTR2A/C-dependent mitochondrial biogenesis and metabolism, which is triggered by adenylyl cyclase/PKA, enhancing the oxidation of lactate within these cells.ConclusionsWe showed that serotonin, through 5-HTR2A/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.

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Produced by several types of tumours, the role of serotonin on cancer biology is yet to be understood
Since protein kinase A (PKA) is reported to promote the expression of PGC1α, a nodal regulator of mitochondrial biogenesis,[54] via CREB phosphorylation, we investigated the expression of this coregulator
Since we characterised that 5-HT signalling via this receptor alters breast cancer cell metabolism towards highly glycolytic and highly oxidative, through upregulation of pyruvate kinase M2 (PKM2) and mitochondria biogenesis, we propose that these characteristics are directly associated with breast cancer aggressiveness and poor prognosis

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Produced by several types of tumours, the role of serotonin on cancer biology is yet to be understood. 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-HTR2A/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-HTR2A/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. In non-tumoural tissues, serotonin activates glycolysis,[9,10,11] which is considered the major pathway supporting cancer cells metabolism and division.[12]

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