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Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy

Hypomagnesemia is very commonly observed in cancer patients, most frequently in association with therapy with cetuximab (CTX), a monoclonal antibody targeting the epithelial growth factor receptor (EGFR). CTX-induced hypomagnesemia has been ascribed to renal magnesium (Mg) wasting. Here, we sought t...

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Autores principales: Pietropaolo, Giuseppe, Pugliese, Daniela, Armuzzi, Alessandro, Guidi, Luisa, Gasbarrini, Antonio, Rapaccini, Gian Lodovico, Wolf, Federica I., Trapani, Valentina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692710/
https://www.ncbi.nlm.nih.gov/pubmed/33114586
http://dx.doi.org/10.3390/nu12113277
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author Pietropaolo, Giuseppe
Pugliese, Daniela
Armuzzi, Alessandro
Guidi, Luisa
Gasbarrini, Antonio
Rapaccini, Gian Lodovico
Wolf, Federica I.
Trapani, Valentina
author_facet Pietropaolo, Giuseppe
Pugliese, Daniela
Armuzzi, Alessandro
Guidi, Luisa
Gasbarrini, Antonio
Rapaccini, Gian Lodovico
Wolf, Federica I.
Trapani, Valentina
author_sort Pietropaolo, Giuseppe
collection PubMed
description Hypomagnesemia is very commonly observed in cancer patients, most frequently in association with therapy with cetuximab (CTX), a monoclonal antibody targeting the epithelial growth factor receptor (EGFR). CTX-induced hypomagnesemia has been ascribed to renal magnesium (Mg) wasting. Here, we sought to clarify whether CTX may also influence intestinal Mg absorption and if Mg supplementation may interfere with CTX activity. We used human colon carcinoma CaCo-2 cells as an in vitro model to study the mechanisms underlying Mg transport and CTX activity. Our findings demonstrate that TRPM6 is the key channel that mediates Mg influx in intestinal cells and that EGF stimulates such influx; consequently, CTX downregulates TRPM6-mediated Mg influx by interfering with EGF signaling. Moreover, we show that Mg supplementation does not modify either the CTX IC50 or CTX-dependent inhibition of ERK1/2 phosphorylation. Our results suggest that reduced Mg absorption in the intestine may contribute to the severe hypomagnesemia that occurs in CTX-treated patients, and Mg supplementation may represent a safe and effective nutritional intervention to restore Mg status without impairing the CTX efficacy.
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spelling pubmed-76927102020-11-28 Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy Pietropaolo, Giuseppe Pugliese, Daniela Armuzzi, Alessandro Guidi, Luisa Gasbarrini, Antonio Rapaccini, Gian Lodovico Wolf, Federica I. Trapani, Valentina Nutrients Article Hypomagnesemia is very commonly observed in cancer patients, most frequently in association with therapy with cetuximab (CTX), a monoclonal antibody targeting the epithelial growth factor receptor (EGFR). CTX-induced hypomagnesemia has been ascribed to renal magnesium (Mg) wasting. Here, we sought to clarify whether CTX may also influence intestinal Mg absorption and if Mg supplementation may interfere with CTX activity. We used human colon carcinoma CaCo-2 cells as an in vitro model to study the mechanisms underlying Mg transport and CTX activity. Our findings demonstrate that TRPM6 is the key channel that mediates Mg influx in intestinal cells and that EGF stimulates such influx; consequently, CTX downregulates TRPM6-mediated Mg influx by interfering with EGF signaling. Moreover, we show that Mg supplementation does not modify either the CTX IC50 or CTX-dependent inhibition of ERK1/2 phosphorylation. Our results suggest that reduced Mg absorption in the intestine may contribute to the severe hypomagnesemia that occurs in CTX-treated patients, and Mg supplementation may represent a safe and effective nutritional intervention to restore Mg status without impairing the CTX efficacy. MDPI 2020-10-26 /pmc/articles/PMC7692710/ /pubmed/33114586 http://dx.doi.org/10.3390/nu12113277 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pietropaolo, Giuseppe
Pugliese, Daniela
Armuzzi, Alessandro
Guidi, Luisa
Gasbarrini, Antonio
Rapaccini, Gian Lodovico
Wolf, Federica I.
Trapani, Valentina
Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy
title Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy
title_full Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy
title_fullStr Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy
title_full_unstemmed Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy
title_short Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy
title_sort magnesium absorption in intestinal cells: evidence of cross-talk between egf and trpm6 and novel implications for cetuximab therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692710/
https://www.ncbi.nlm.nih.gov/pubmed/33114586
http://dx.doi.org/10.3390/nu12113277
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