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N-Myc-induced up-regulation of TRPM6/TRPM7 channels promotes neuroblastoma cell proliferation
Zheng Zhang1, Malika Faouzi2, Junhao Huang3
1Center 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.
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.
Insights
The MYCN oncogene promotes neuroblastoma growth by increasing calcium (Ca2+) and magnesium (Mg2+) uptake. This occurs through enhanced expression and function of TRPM6 and TRPM7 channel kinases, crucial for cell proliferation.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Intracellular calcium (Ca2+) and magnesium (Mg2+) are vital for cell cycle regulation and proliferation.
- Dysregulation of these divalent cations is implicated in cancer.
- The TRPM6 and TRPM7 channel kinases are key regulators of Ca2+/Mg2+ homeostasis.
Purpose of the Study:
- To investigate the role of the MYCN oncogene in regulating TRPM6 and TRPM7 expression and function in neuroblastoma.
- To understand the impact of N-Myc on Ca2+ and Mg2+ transport in cancer cells.
Main Methods:
- Utilized the SHEP-21N human neuroblastoma cell line with inducible MYCN expression.
- Performed membrane current analyses to characterize TRPM6/TRPM7 channel activity.
- Employed small interfering RNA (siRNA) to genetically suppress TRPM6/TRPM7 expression.
Main Results:
- N-Myc expression significantly increased cell growth and upregulated both TRPM6 and TRPM7 expression.
- Endogenous TRPM6/TRPM7 channels showed altered properties, including reduced Mg·ATP suppression and increased Mg2+ sensitivity.
- Genetic suppression of TRPM6/TRPM7 inhibited N-Myc-driven cell proliferation.
Conclusions:
- N-Myc promotes neuroblastoma proliferation by upregulating TRPM6 and TRPM7 channels.
- These channels facilitate increased Ca2+ and Mg2+ uptake, contributing to cancer cell growth.
- Targeting TRPM6/TRPM7 may offer a therapeutic strategy for MYCN-driven neuroblastomas.
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