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Membrane protein CNNM4–dependent Mg2+ efflux suppresses tumor progression
Yosuke Funato, … , Kazuya Kikuchi, Hiroaki Miki
Yosuke Funato, … , Kazuya Kikuchi, Hiroaki Miki
Published October 27, 2014
Citation Information: J Clin Invest. 2014;124(12):5398-5410. https://doi.org/10.1172/JCI76614.
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Research Article Oncology

Membrane protein CNNM4–dependent Mg2+ efflux suppresses tumor progression

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Abstract

Intracellular Mg2+ levels are strictly regulated; however, the biological importance of intracellular Mg2+ levels and the pathways that regulate them remain poorly understood. Here, we determined that intracellular Mg2+ is important in regulating both energy metabolism and tumor progression. We determined that CNNM4, a membrane protein that stimulates Mg2+ efflux, binds phosphatase of regenerating liver (PRL), which is frequently overexpressed in malignant human cancers. Biochemical analyses of cultured cells revealed that PRL prevents CNNM4-dependent Mg2+ efflux and that regulation of intracellular Mg2+ levels by PRL and CNNM4 is linked to energy metabolism and AMPK/mTOR signaling. Indeed, treatment with the clinically available mTOR inhibitor rapamycin suppressed the growth of cancer cells in which PRL was overexpressed. In ApcΔ14/+ mice, which spontaneously form benign polyps in the intestine, deletion of Cnnm4 promoted malignant progression of intestinal polyps to adenocarcinomas. IHC analyses of tissues from patients with colon cancer demonstrated an inverse relationship between CNNM4 expression and colon cancer malignancy. Together, these results indicate that CNNM4-dependent Mg2+ efflux suppresses tumor progression by regulating energy metabolism.

Authors

Yosuke Funato, Daisuke Yamazaki, Shin Mizukami, Lisa Du, Kazuya Kikuchi, Hiroaki Miki

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Figure 7

PRL promotes tumor growth via CNNM4.

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PRL promotes tumor growth via CNNM4.
(A) B16 cells stably expressing Myc...
(A) B16 cells stably expressing Myc-PRL3 were subjected to tumor-formation experiments. The number of tumor nodules on the lungs is shown as the mean ± SEM (n = 15; 3 independent cell clones for each construct). *P < 0.05 by ANOVA, followed by 2-tailed multiple Student’s t test with Bonferroni’s correction. Scale bar: 2 mm. (B) Cnnm4 RNAi B16 cells were subjected to tumor-formation experiments. Results represent the mean ± SEM. n = 6 (control or Cav2 RNAi) or n = 12 (Cnnm4 RNAi), with 3 independently obtained cells for each construct. *P < 0.05 by ANOVA, followed by 2-tailed multiple Student’s t test with Bonferroni’s correction. Representative immunoblot results for endogenous CNNM4 (from 3 independent experiments) are also shown. (C) B16 cells stably expressing PRL3-WT were subjected to tumor-formation experiments, with rapamycin (7.5 mg/kg/day) or PD98059 (3.0 mg/kg/day) treatment started from the day following cell inoculation (mean ± SEM, n = 6). *P < 0.05 by paired 2-tailed Student’s t test.

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