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Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells

Melatonin has been reported to induce effective reduction in growth and development in a variety of tumors, including breast cancer. In triple-negative breast cancer (TNBC) cells, melatonin attenuates a variety of cancer features, such as tumor growth and apoptosis resistance, through a number of st...

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Autores principales: Jardin, Isaac, Diez-Bello, Raquel, Falcon, Debora, Alvarado, Sandra, Regodon, Sergio, Salido, Gines M., Smani, Tarik, Rosado, Juan A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948746/
https://www.ncbi.nlm.nih.gov/pubmed/33380424
http://dx.doi.org/10.1074/jbc.RA120.015769
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author Jardin, Isaac
Diez-Bello, Raquel
Falcon, Debora
Alvarado, Sandra
Regodon, Sergio
Salido, Gines M.
Smani, Tarik
Rosado, Juan A.
author_facet Jardin, Isaac
Diez-Bello, Raquel
Falcon, Debora
Alvarado, Sandra
Regodon, Sergio
Salido, Gines M.
Smani, Tarik
Rosado, Juan A.
author_sort Jardin, Isaac
collection PubMed
description Melatonin has been reported to induce effective reduction in growth and development in a variety of tumors, including breast cancer. In triple-negative breast cancer (TNBC) cells, melatonin attenuates a variety of cancer features, such as tumor growth and apoptosis resistance, through a number of still poorly characterized mechanisms. One biological process that is important for TNBC cells is store-operated Ca(2+) entry (SOCE), which is modulated by TRPC6 expression and function. We wondered whether melatonin might intersect with this pathway as part of its anticancer activity. We show that melatonin, in the nanomolar range, significantly attenuates TNBC MDA-MB-231 cell viability, proliferation, and migration in a time- and concentration-dependent manner, without having any effect on nontumoral breast epithelial MCF10A cells. Pretreatment with different concentrations of melatonin significantly reduced SOCE in MDA-MB-231 cells without altering Ca(2+) release from the intracellular stores. By contrast, SOCE in MCF10A cells was unaffected by melatonin. In the TNBC MDA-MB-468 cell line, melatonin not only attenuated viability, migration, and SOCE, but also reduced TRPC6 expression in a time- and concentration-dependent manner, without altering expression or function of the Ca(2+) channel Orai1. The expression of exogenous TRPC6 overcame the effect of melatonin on SOCE and cell proliferation, and silencing or inhibition of TRPC6 impaired the inhibitory effect of melatonin on SOCE. These findings indicate that TRPC6 downregulation might be involved in melatonin's inhibitory effects on Ca(2+) influx and the maintenance of cancer hallmarks and point toward a novel antitumoral mechanism of melatonin in TNBC cells.
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spelling pubmed-79487462021-03-19 Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells Jardin, Isaac Diez-Bello, Raquel Falcon, Debora Alvarado, Sandra Regodon, Sergio Salido, Gines M. Smani, Tarik Rosado, Juan A. J Biol Chem Research Article Melatonin has been reported to induce effective reduction in growth and development in a variety of tumors, including breast cancer. In triple-negative breast cancer (TNBC) cells, melatonin attenuates a variety of cancer features, such as tumor growth and apoptosis resistance, through a number of still poorly characterized mechanisms. One biological process that is important for TNBC cells is store-operated Ca(2+) entry (SOCE), which is modulated by TRPC6 expression and function. We wondered whether melatonin might intersect with this pathway as part of its anticancer activity. We show that melatonin, in the nanomolar range, significantly attenuates TNBC MDA-MB-231 cell viability, proliferation, and migration in a time- and concentration-dependent manner, without having any effect on nontumoral breast epithelial MCF10A cells. Pretreatment with different concentrations of melatonin significantly reduced SOCE in MDA-MB-231 cells without altering Ca(2+) release from the intracellular stores. By contrast, SOCE in MCF10A cells was unaffected by melatonin. In the TNBC MDA-MB-468 cell line, melatonin not only attenuated viability, migration, and SOCE, but also reduced TRPC6 expression in a time- and concentration-dependent manner, without altering expression or function of the Ca(2+) channel Orai1. The expression of exogenous TRPC6 overcame the effect of melatonin on SOCE and cell proliferation, and silencing or inhibition of TRPC6 impaired the inhibitory effect of melatonin on SOCE. These findings indicate that TRPC6 downregulation might be involved in melatonin's inhibitory effects on Ca(2+) influx and the maintenance of cancer hallmarks and point toward a novel antitumoral mechanism of melatonin in TNBC cells. American Society for Biochemistry and Molecular Biology 2021-01-08 /pmc/articles/PMC7948746/ /pubmed/33380424 http://dx.doi.org/10.1074/jbc.RA120.015769 Text en © 2021 THE AUTHORS https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Jardin, Isaac
Diez-Bello, Raquel
Falcon, Debora
Alvarado, Sandra
Regodon, Sergio
Salido, Gines M.
Smani, Tarik
Rosado, Juan A.
Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells
title Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells
title_full Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells
title_fullStr Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells
title_full_unstemmed Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells
title_short Melatonin downregulates TRPC6, impairing store-operated calcium entry in triple-negative breast cancer cells
title_sort melatonin downregulates trpc6, impairing store-operated calcium entry in triple-negative breast cancer cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948746/
https://www.ncbi.nlm.nih.gov/pubmed/33380424
http://dx.doi.org/10.1074/jbc.RA120.015769
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