Magnesium deficiency with high calcium-to-magnesium ratio promotes a metastatic phenotype in the CT26 colon cancer cell line

Abstract

Magnesium (Mg) plays important roles in maintaining genomic stability and cellular redox. Mg also serves as nature's physiological calcium (Ca) channel antagonist, controlling intracellular Ca entry. Because Ca is the most important second messenger, its intracellular concentration is tightly regulated. Excess intracellular Ca can activate aberrant signaling pathways leading to the acquisition of pathological characteristics and cell injury. Several epidemiological studies have linked Mg deficiency (MgD) and increased Ca:Mg ratios with higher incidences of colon cancer and increased mortality. While it is estimated that less than 50% of the US population consumes the recommended daily allowance for Mg, Ca supplementation is widespread. Therefore, we studied the effect of MgD, with variable Ca:Mg ratios on cellular oxidative stress, cell migration, calpain activity, and associated signaling pathways using the CT26 colon cancer cell line. MgD (with Ca:Mg ratios >1) elevated intracellular Ca levels, calpain activity and TRPM7 expression, as well as oxidative stress and cell migration, consistent with observed degradation of fulllength E-cadherin, b-catenin, and N-terminal FAK. MgD was accompanied by enhanced degradation of IkBa and the transactivation domain containing the Cterminus of NF-kB p65 (RelA). MgD-exposed CT26 cells exhibited increased p53 degradation and aneuploidy, markers of genomic instability. By contrast, these pathological changes were not observed when CT26 were cultured under MgD conditions where the Ca:Mg ratio was kept at 1. Together, these data support that exposure of colon cancer cells to MgD with physiological Ca concentrations (or increasing Ca:Mg ratios) leads to the acquisition of a more aggressive, metastatic phenotype.

Magnesium supplementation reduces inflammation in rats with induced chronic kidney disease

“…Previous studies aimed at addressing mechanistic insights on the protective effect of Mg on vascular cells gave relevance to the properties of Mg as a calcium antagonist, 1 so that calcium action is susceptible of being modified by the Mg supplement. A rise in the intracellular calcium can activate transduction pathways leading to an increase in oxidative stress, the activation of the NF‐κB signalling and the production of pro‐inflammatory cytokines 49,50 . Thus, as a physiological inhibitor of calcium channels, Mg might prevent calcium flux and therefore the inflammatory response.…”

“…Thus, a Ca/Mg ratio between 1.70 and 2.6 may be required for high intakes of Ca and Mg to be protective (62). Interestingly, a recent in vitro study using the CT26 colon cancer cell line showed that with Ca/Mg ratios >1, Mg deficiency resulted in oxidative stress and NF-κB p65 activation, while this was not observed with a Ca/Mg ratio of 1 (50). Though a possible modifying effect of the Ca/Mg intake ratio cannot be totally discarded in our in vivo model, it would not likely be much relevant as it is usually important when magnesium or calcium are provided in deficient or barely adequate amounts, which is not the case.…”

Employing Piezoelectric Mg2+‐Doped Hydroxyapatite to Target Death Receptor‐Mediated Necroptosis: A Strategy for Amplifying Immune Activation

“…These outcomes were more pronounced in the metastatic group, suggesting a potential association between Mg 2+ release and the inhibition of distant colorectal cancer metastasis. [ 33 ] Subsequently, we quantified the number of infiltrating immune cells at primary and metastatic sites. Notably, effector T (CD45 + , CD3 + , and CD8 + ) and cytotoxic T cells (CD3 + , CD8 + , and IFN‐γ + ) were markedly elevated in the MHM and MHMO groups at the primary location, with infiltration further accentuated following piezoelectric stimulation (Figure 5d–g ).…”

The Role of TRPM7 in Oncogenesis

“…The calcium/magnesium intake ratio and their balance regulated by parathyroid hormone and TRPM7 have been implicated in the development of colorectal carcinoma [141,142]. Furthermore, magnesium deficiency with physiological Ca 2+ concentrations (i.e., increased Ca 2+ /Mg 2+ ratio) was associated with increased TRPM7 expression, oxidative stress, induced calpain activity, increased cell migration and a more aggressive, metastatic phenotype of colon cancer cells [143] (Table 6).…”