title: N-Myc-induced up-regulation of TRPM6/TRPM7 channels promotes neuroblastoma cell proliferation.
abstract: Intracellular levels of the divalent cations Ca2+ and Mg2+ are important regulators of cell cycle and proliferation. However, the precise mechanisms by which they are regulated in cancer remain incompletely understood. The channel kinases TRPM6 and TRPM7 are gatekeepers of human Ca2+/Mg2+ metabolism. Here, we investigated the human neuroblastoma cell line SHEP-21N in which the MYCN oncogene (encoding N-Myc) can be reversibly expressed under control of an inducible repressor. We report that N-Myc expression increases cell growth and up-regulates both TRPM6 and TRPM7 expression. Membrane current analyses reveal that endogenous TRPM6/TRPM7 currents exhibit reduced Mg·ATP suppression, increased Mg2+ sensitivity, and diminished sensitivity to 2-APB inhibition. These properties are consistent with N-Myc-induced increase of heteromeric TRPM7/TRPM6 channels promoting Ca2+ and Mg2+ uptake. Genetic suppression of TRPM6/TRPM7 through siRNA inhibits cell proliferation, suggesting that N-Myc can promote neuroblastoma cell proliferation through up-regulation of divalent cation-transporting channels.
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center, University of Hawaii Cancer Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, U.S.A. Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China. Contributed equally to this work.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center, University of Hawaii Cancer Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, U.S.A.. Contributed equally to this work.
authors.forename: Malika
authors.initials: M
authors.lastname: Faouzi
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center, University of Hawaii Cancer Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, U.S.A.
authors.forename: Junhao
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Dr. Molewaterplein 50, GE Rotterdam, the Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Geerts
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center, University of Hawaii Cancer Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, U.S.A.
authors.forename: Haijie
authors.initials: H
authors.lastname: Yu
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center,University of Hawaii Cancer Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, U.S.A.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fleig
authors.affiliation: Center for Biomedical Research, The Queen's Medical Center, University of Hawaii Cancer Center and John A. Burns School of Medicine, University of Hawaii, Honolulu, U.S.A.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Penner
mesh_terms: D002413:Cations, Divalent / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D050053:TRPM Cation Channels / Q000096:biosynthesis*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D002413:Cations, Divalent; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human