Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice

Huang, Junhao; Furuya, Hideki; Faouzi, Malika; Zhang, Zheng; Monteilh-Zoller, Mahealani K.; Kawabata, Kelly Galbraith; Horgen, F. David; Kawamori, Toshihiko; Penner, Reinhold; Fleig, Andrea

doi:10.1186/s12964-017-0187-9

Cited by 25 publications

(16 citation statements)

References 35 publications

(66 reference statements)

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“…The properties of TRPM7 as the channel and kinase and compensatory maintenance of Mg 2+ homeostasis causes the difficulties for revealing the roles of Mg 2+ in animal developments. Recently, some groups have shown that inactivation of the TRPM7 channel in living mice results in impaired Mg 2+ transport, supporting the notion that the TRPM7 channel indeed can function as important Mg 2+ channel in vivo [165,169]. Moreover, careful analysis using TRPM7 mutants lacking kinase domain support that TRPM7-mediated Mg 2+ influx is essential for embryonic developments in vertebrate [10,170].…”

Section: Effects Of Mg2+ On the Cellular Fate And Phenotypementioning

confidence: 92%

Magnesium Is a Key Player in Neuronal Maturation and Neuropathology

Yamanaka

Shindo

Oka

2019

IJMS

106

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Magnesium (Mg) is the second most abundant cation in mammalian cells, and it is essential for numerous cellular processes including enzymatic reactions, ion channel functions, metabolic cycles, cellular signaling, and DNA/RNA stabilities. Because of the versatile and universal nature of Mg2+, the homeostasis of intracellular Mg2+ is physiologically linked to growth, proliferation, differentiation, energy metabolism, and death of cells. On the cellular and tissue levels, maintaining Mg2+ within optimal levels according to the biological context, such as cell types, developmental stages, extracellular environments, and pathophysiological conditions, is crucial for development, normal functions, and diseases. Hence, Mg2+ is pathologically involved in cancers, diabetes, and neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, and demyelination. In the research field regarding the roles and mechanisms of Mg2+ regulation, numerous controversies caused by its versatility and complexity still exist. As Mg2+, at least, plays critical roles in neuronal development, healthy normal functions, and diseases, appropriate Mg2+ supplementation exhibits neurotrophic effects in a majority of cases. Hence, the control of Mg2+ homeostasis can be a candidate for therapeutic targets in neuronal diseases. In this review, recent results regarding the roles of intracellular Mg2+ and its regulatory system in determining the cell phenotype, fate, and diseases in the nervous system are summarized, and an overview of the comprehensive roles of Mg2+ is provided.

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Section: Effects Of Mg2+ On the Cellular Fate And Phenotypementioning

confidence: 92%

Magnesium Is a Key Player in Neuronal Maturation and Neuropathology

Yamanaka

Shindo

Oka

2019

IJMS

106

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“…Administration of NS8593 in vivo could lead to perturbances in the systemic divalent cation homeostasis due to suppression of TRPM7-dependent uptake of minerals in the colon, as has previously shown for waixenicin A, a natural product inhibitor of TRPM7 derived from Sarcothelia edmonsoni 35 . It will be interesting to see whether the protective effect of TRPM7 suppression in kidney fibrosis is mainly due to TRPM7 channel or kinase activity itself, a likely hypomagnesemia induction (or divalent perturbance), or a combination thereof.…”

Section: Discussionmentioning

confidence: 78%

TRPM7 contributes to progressive nephropathy

Suzuki

Penner

Fleig

2020

Sci Rep

Self Cite

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TRPM7 belongs to the Transient Receptor Potential Melastatin family of ion channels and is a divalent cation-conducting ion channel fused with a functional kinase. TRPM7 plays a key role in a variety of diseases, including neuronal death in ischemia, cancer, cardiac atrial fibrillation, malaria invasion. TRPM7 is aberrantly over-expressed in lung, liver and heart fibrosis. It is also overexpressed after renal ischemia-reperfusion, an event that induces kidney injury and fibrosis. However, the role of TRPM7 in kidney fibrosis is unclear. Using the unilateral ureteral obstruction (UUO) mouse model, we examined whether TRPM7 contributes to progressive renal damage and fibrosis. We find that TRPM7 expression increases in UUO kidneys. Systemic application of NS8593, a known TRPM7 inhibitor, prevents kidney atrophy in UUO kidneys, retains tubular formation, and reduces TRPM7 expression to normal levels. Cell proliferation of both tubular epithelial cells and interstitial cells is reduced by NS8593 treatment in UUO kidneys, as are TGF-β1/Smad signaling events. We conclude that TRPM7 is upregulated during inflammatory renal damage and propose that pharmacological intervention targeting TRPM7 may prove protective in progressive kidney fibrosis.TRPM7 belongs to the Transient Receptor Potential (TRP) Melastatin family of ion channels, but is unique in that its ion channel domain is fused with a functional serine/threonine kinase 1 . TRPM7 was the first ion channel shown to conduct a range of divalent cations 2,3 , including physiologically essential divalent cations such as Ca 2+ , Mg 2+ , Zn 2+ , Ni 2+ , Mn 2+ , and Co 2+ . Ample evidence supports TRPM7 to be critical in regulating Mg 2+ homeostasis 1 and play a key role in a variety of diseases, including neuronal death in ischemia 4 , renal ischemia 5 , and cardiac atrial fibrillation 6 . TRPM7 is expressed ubiquitously in mammals, and is key in driving cell growth and proliferation, linking the protein to hyperproliferative diseases such cancer 1,7,8 and pulmonary, hepatic, and cardiac fibrosis 6,9-12 . Tissue fibrosis refers to a number of conditions that cause interstitial organ damage followed by inflammation and maladaptive wound healing eventually leading to fibrosis and chronic disease in the organ affected. TRPM7 overexpression leads to fibrosis through the TGF-β signaling pathway 9-11 . Recent in vitro data show that TRPM7 plays a pivotal role in progressive inflammatory and fibrotic disease by promoting excessive extracellular matrix (ECM) deposition 9 . It regulates proliferation and differentiation of fibroblasts 11 and proliferation and polarization of macrophages 13 as well as their Ca 2+ -dependent activation 14 . A recent study supports this hypothesis, as genetic suppression of TRPM7 in a kidney transplantation mouse model alleviated progressive inflammatory kidney fibrosis 15 .In the kidney, cell proliferation is a central response to injury that culminates in the development of fibrosis and renal failure. Unilateral ureteral obstruction (UUO) is a wide...

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“…One concern for this study is that there is no ideal specific TRPM7 inhibitor. We screened several TRPM7 inhibitors, 2-APB, Gin Rd, and Waix A, but none of these inhibitors are specific to TRPM7: (a) 2-APB affects inositol 1,4,5-trisphosphate receptors, store-operated calcium channels and TRP channels, TRPV3 and TRPM7 [16,27]; (b) Gin Rd affects TRPM channels, acid-sensing ion channels (ASIC), and some cation channels [17,28]; (c) Waix A is a newly identified TRPM7 inhibitor [29,30]. Although Waix A does not inhibit TRPM2, TRPM4, TRPM6 or CRAC channels, its potency depends on the intracellular Mg 2+ concentration and it is known to affect some cell lines that do not express TRPM7 [18,30].…”

Section: Discussionmentioning

confidence: 99%

The Role of Transient Receptor Potential Melastatin 7 (TRPM7) in Cell Viability: A Potential Target to Suppress Breast Cancer Cell Cycle

Liu

Dilger

Lin

2020

Cancers

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The divalent cation-selective channel transient receptor potential melastatin 7 (TRPM7) channel was shown to affect the proliferation of some types of cancer cell. However, the function of TRPM7 in the viability of breast cancer cells remains unclear. Here we show that TRPM inhibitors suppressed the viability of TRPM7-expressing breast cancer cells. We first demonstrated that the TRPM7 inhibitors 2-aminoethyl diphenylborinate (2-APB), ginsenoside Rd (Gin Rd), and waixenicin A preferentially suppressed the viability of human embryonic kidney HEK293 overexpressing TRPM7 (HEK-M7) cells over wildtype HEK293 (WT-HEK). Next, we confirmed the effects of 2-APB on the TRPM7 channel functions by whole-cell currents and divalent cation influx. The inhibition of the viability of HEK-M7 cells by 2-APB was not mediated by the increase in cell death but by the interruption of the cell cycle. Similar to HEK-M7 cells, the viability of TRPM7-expressing human breast cancer MDA-MB-231, AU565, and T47D cells were also suppressed by 2-APB by arresting the cell cycle in the S phase. Furthermore, in a novel TRPM7 knock-out MDA-MB-231 (KO-231) cell line, decreased divalent influx and reduced proliferation were observed compared to the wildtype MDA-MB-231 cells. 2-APB and Gin Rd preferentially suppressed the viability of wildtype MDA-MB-231 cells over KO-231 by affecting the cell cycle in wildtype but not KO-231 cells. Our results suggest that TRPM7 regulates the cell cycle of breast cancers and is a potential therapeutic target.

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Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice

Cited by 25 publications

References 35 publications

Magnesium Is a Key Player in Neuronal Maturation and Neuropathology

Magnesium Is a Key Player in Neuronal Maturation and Neuropathology

TRPM7 contributes to progressive nephropathy

The Role of Transient Receptor Potential Melastatin 7 (TRPM7) in Cell Viability: A Potential Target to Suppress Breast Cancer Cell Cycle

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