RRC ID 78449
Author Funato Y, Yamazaki D, Mizukami S, Du L, Kikuchi K, Miki H.
Title Membrane protein CNNM4-dependent Mg2+ efflux suppresses tumor progression.
Journal J Clin Invest
Abstract Intracellular Mg(2+) levels are strictly regulated; however, the biological importance of intracellular Mg(2+) levels and the pathways that regulate them remain poorly understood. Here, we determined that intracellular Mg(2+) is important in regulating both energy metabolism and tumor progression. We determined that CNNM4, a membrane protein that stimulates Mg(2+) 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 Mg(2+) efflux and that regulation of intracellular Mg(2+) 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 ApcΔ(14/+) 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 Mg(2+) efflux suppresses tumor progression by regulating energy metabolism.
Volume 124(12)
Pages 5398-410
Published 2014-12-1
DOI 10.1172/JCI76614
PII 76614
PMID 25347473
PMC PMC4348944
MeSH AMP-Activated Protein Kinases / genetics AMP-Activated Protein Kinases / metabolism Adenocarcinoma / genetics Adenocarcinoma / metabolism* Adenocarcinoma / pathology Animals Antibiotics, Antineoplastic / pharmacology Cation Transport Proteins / genetics Cation Transport Proteins / metabolism* Colonic Neoplasms / genetics Colonic Neoplasms / metabolism* Colonic Neoplasms / pathology Colonic Polyps / genetics Colonic Polyps / metabolism Colonic Polyps / pathology Energy Metabolism / drug effects Energy Metabolism / genetics Gene Expression Regulation, Neoplastic* Humans Ion Transport / genetics Magnesium / metabolism* Mice Mice, Knockout Neoplasm Proteins / genetics Neoplasm Proteins / metabolism* Neoplasms, Experimental / genetics Neoplasms, Experimental / metabolism* Neoplasms, Experimental / pathology Signal Transduction / drug effects Signal Transduction / genetics Sirolimus / pharmacology TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism
Mice RBRC01872