N-Myc-induced up-regulation of TRPM6/TRPM7 channels promotes neuroblastoma cell proliferation

Zheng Zhang, Malika Faouzi, Junhao Huang, Dirk Geerts, Haijie Yu, Andrea Fleig, Reinhold Penner

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)7625-34
Number of pages10
JournalOncotarget
Volume5
Issue number17
DOIs
Publication statusPublished - 15 Sep 2014

Keywords

  • Cations, Divalent/metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Gene Expression Regulation, Neoplastic/genetics
  • Humans
  • Neuroblastoma/genetics
  • Patch-Clamp Techniques
  • Protein Serine-Threonine Kinases/biosynthesis
  • Proto-Oncogene Proteins c-myc/metabolism
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • TRPM Cation Channels/biosynthesis
  • Transfection
  • Up-Regulation

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