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

Giuseppe Pietropaolo,Luisa Guidi,Daniela Pugliese,Alessandro Armuzzi,Antonio Gasbarrini,Valentina Trapani,Gian Lodovico Rapaccini,Federica I Wolf

doi:10.3390/nu12113277

Abstract

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.

Highlights

Nutritional deficits, defined as an imbalance between intake and metabolic requirements, are very common in cancer patients and may be caused by both the tumor itself and its treatment [1]
To determine whether the detected Mg influx is mediated by TRPM6, we repeated the same experiment in TRPM6-silenced
The induces interference between the mode of actionantagonistic of CTX andeffect the generalized electrolyte wasting hypomagnesemia by a specific homeostatic of Mg has notthe received the deserved attention to itsofclinical

Summary

Introduction

Nutritional deficits, defined as an imbalance between intake and metabolic requirements, are very common in cancer patients and may be caused by both the tumor itself and its treatment [1]. Several meta-analyses have shown that the incidence of all-grade hypomagnesemia in CTX-treated patients could be as high as about 35%; in about 5% of Nutrients 2020, 12, 3277; doi:10.3390/nu12113277 www.mdpi.com/journal/nutrients. Early hypomagnesemia seems to act as a good predictor of the efficacy and outcome of CTX in KRAS wild-type CRC patients [9]. Opposing results have been reported [10], a recent meta-analysis confirmed that hypomagnesemia is associated with better progression-free survival, overall survival, and overall relative risk in CTX-treated KRAS wild-type CRC patients [11]. In addition to the clinical relevance of these findings, Vincenzi et al [12]

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Conclusion