Cancer Metabolism

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

Abstract

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-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.

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.

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Acknowledgements

Authors thank Dr. Patricia L. Mitchel (Université Laval, Quebec, Canada) and Dr. Wassim Abu-Kheir (American University of Beirut, Lebanon) for critical reading of the paper and Dr. Gregg L. Semenza (Johns Hopkins University School of Medicine, Baltimore, MD, USA) for discussion of the data. Authors also thank Dr. Bruno Diaz (IBCCF, UFRJ, Brazil), Dr. Julia Clarke (FF, UFRJ, Brazil), Dr. Marcelo T. Bozza (IMPG, UFRJ, Brazil), Dr. Nathalia Meireles (INCa, Brazil) and Dr. Sergio T. Ferreira (IBCCF, UFRJ, Brazil) for contributing with analytical tools to this work.

Author information

M.S.-P. and P.Z. designed research; M.S.-P., L.P.P., J.R.B., A.C.O., J.M.A., D.M.M., W.S.C., M.C.M. and P.Z. performed research; C.P.F. and D.B.-d.-S. contributed new analytical tools; M.S.-P. and P.Z. analysed the data and wrote the paper.

Correspondence to Patricia Zancan.

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The work was supported by grants from FAPERJ (M.S.-P. and P.Z.) and CNPq (M.S.-P. and P.Z.).

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All pertinent data to support this study are included in the paper and supplementary files. Further data supporting the findings are available upon request.

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Sola-Penna, M., Paixão, L.P., Branco, J.R. et al. Serotonin activates glycolysis and mitochondria biogenesis in human breast cancer cells through activation of the Jak1/STAT3/ERK1/2 and adenylate cyclase/PKA, respectively. Br J Cancer 122, 194–208 (2020). https://doi.org/10.1038/s41416-019-0640-1

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