Upregulation of Chemoresistance by Mg2+ Deficiency through Elevation of ATP Binding Cassette Subfamily B Member 1 Expression in Human Lung Adenocarcinoma A549 Cells.

Saki Onuma,Akira Ikari,Yuta Yoshino,Toshiyuki Matsunaga,Tomohiro Asai,Aya Manabe

doi:10.3390/cells10051179

Abstract

Several anticancer drugs including cisplatin (CDDP) induce hypomagnesemia. However, it remains fully uncertain whether Mg2+ deficiency affects chemosensitivity of cancer cells. Here, we investigated the effect of low Mg2+ concentration (LM) on proliferation and chemosensitivity using human lung adenocarcinoma A549 cells. Cell proliferation was reduced by continuous culture with LM accompanied with the elevation of G1 phase proportion. The amounts of reactive oxygen species (ROS) and stress makers such as phosphorylated-ataxia telangiectasia mutated and phosphorylated-p53 were increased by LM. Cell injury was dose-dependently increased by anticancer drugs such as CDDP and doxorubicin (DXR), which were suppressed by LM. Similar results were obtained by roscovitine, a cell cycle inhibitor. These results suggest that LM induces chemoresistance mediated by ROS production and G1 arrest. The mRNA and protein levels of ATP binding cassette subfamily B member 1 (ABCB1) were increased by LM and roscovitine. The LM-induced elevation of ABCB1 and nuclear p38 expression was suppressed by SB203580, a p38 MAPK inhibitor. PSC833, an ABCB1 inhibitor, and SB203580 rescued the sensitivity to anticancer drugs. In addition, cancer stemness properties were suppressed by SB203580. We suggest that Mg2+ deficiency reduces the chemotherapy sensitivity of A549 cells, although it suppresses cell proliferation.

Highlights

Magnesium (Mg2+ ) is the fourth most abundant cation in the body and an essential electrolyte with various physiological functions
These results indicate that the gap 1 (G1)-S cell cycle progression may be suppressed by low Mg2+ concentration (LM)
The protein level of ATP binding cassette subfamily B member 1 (ABCB1) was increased by roscovitine (Figure 5C). These results indicate that the expression of ABCB1 may be controlled by cell cycle regulators

Summary

Introduction

Magnesium (Mg2+ ) is the fourth most abundant cation in the body and an essential electrolyte with various physiological functions. Mg2+ deficiency can be induced by poor oral intake, increased renal loss, and chronic diarrhea. Loss-of-function mutations in the human transient receptor potential melastatin 6 (TRPM6) cause hereditary hypomagnesemia and secondary hypocalcemia [2]. In a nested case-control study, high and low serum Mg2+ concentrations are associated with an increased incident risk of cancer [3]. Lower expression level of TRPM6 is associated with poor prognosis in patients with colorectal, breast gastric, and lung cancers [4]. Some anticancer drugs, including cisplatin (CDDP), a platinum based anticancer drug, and cetuximab and panitumumab, chimeric and fully human monoclonal antibodies to the epidermal growth factor receptor (EGFR), often cause a side effect of hypomagnesemia [5].

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