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

doi:10.18632/oncotarget.2283

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Research Papers:

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 and Reinhold Penner _

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Oncotarget. 2014; 5:7625-7634. https://doi.org/10.18632/oncotarget.2283

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Abstract

Zheng Zhang1,3,*, Malika Faouzi1,*, Junhao Huang1, Dirk Geerts2, Haijie Yu1, Andrea Fleig1 and Reinhold Penner1

1 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

2 Department of Pediatric Oncology/Hematology, Erasmus University Medical Center, Dr. Molewaterplein 50, GE Rotterdam, the Netherlands

3 Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China

* These authors contributed equally to this work

Correspondence:

Reinhold Penner, email:

Andrea Fleig, email:

Keywords: cancer/magnesium/neuroblastoma/N-Myc/TRPM6/TRPM7

Received: May 28, 2014 Accepted: July 31, 2014 Published: July 31, 2014

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.

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Research Papers:

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

Abstract