title: Membrane protein CNNM4-dependent Mg2+ efflux suppresses tumor progression.
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.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Funato
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamazaki
authors.forename: Shin
authors.initials: S
authors.lastname: Mizukami
authors.forename: Lisa
authors.initials: L
authors.lastname: Du
authors.forename: Kazuya
authors.initials: K
authors.lastname: Kikuchi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Miki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003111:Colonic Polyps / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017136:Ion Transport / Q000235:genetics; D008274:Magnesium / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C539261:CNNM4 protein, human; D027682:Cation Transport Proteins; D009363:Neoplasm Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D008274:Magnesium; D020123:Sirolimus