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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doaj-770b9d18b3fd4ba88d776a53dc0f1b3f2020-11-25T03:43:21ZengMDPI AGNutrients2072-66432020-10-01123277327710.3390/nu12113277Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab TherapyGiuseppe Pietropaolo0Daniela Pugliese1Alessandro Armuzzi2Luisa Guidi3Antonio Gasbarrini4Gian Lodovico Rapaccini5Federica I. Wolf6Valentina Trapani7Sezione di Patologia Generale, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, ItalyUOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, ItalyUOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, ItalyUOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, ItalyUOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, ItalyUOC Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, ItalySezione di Patologia Generale, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, ItalySezione di Patologia Generale, Dipartimento di Medicina e Chirurgia Traslazionale, Fondazione Policlinico Universitario A. Gemelli IRCCS—Università Cattolica del Sacro Cuore, 00168 Rome, ItalyHypomagnesemia 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.https://www.mdpi.com/2072-6643/12/11/3277biomarkercolorectal cancerEGFRhypomagnesemiamagnesium supplementationmonoclonal antibodies |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Giuseppe Pietropaolo Daniela Pugliese Alessandro Armuzzi Luisa Guidi Antonio Gasbarrini Gian Lodovico Rapaccini Federica I. Wolf Valentina Trapani |
spellingShingle |
Giuseppe Pietropaolo Daniela Pugliese Alessandro Armuzzi Luisa Guidi Antonio Gasbarrini Gian Lodovico Rapaccini Federica I. Wolf Valentina Trapani Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy Nutrients biomarker colorectal cancer EGFR hypomagnesemia magnesium supplementation monoclonal antibodies |
author_facet |
Giuseppe Pietropaolo Daniela Pugliese Alessandro Armuzzi Luisa Guidi Antonio Gasbarrini Gian Lodovico Rapaccini Federica I. Wolf Valentina Trapani |
author_sort |
Giuseppe Pietropaolo |
title |
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_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_sort |
magnesium absorption in intestinal cells: evidence of cross-talk between egf and trpm6 and novel implications for cetuximab therapy |
publisher |
MDPI AG |
series |
Nutrients |
issn |
2072-6643 |
publishDate |
2020-10-01 |
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. |
topic |
biomarker colorectal cancer EGFR hypomagnesemia magnesium supplementation monoclonal antibodies |
url |
https://www.mdpi.com/2072-6643/12/11/3277 |
work_keys_str_mv |
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