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 (original) (raw)
Related papers
From magnesium to magnesium transporters in cancer: TRPM7, a novel signature in tumour development
2014
Magnesium availability affects many cellular functions that are critical for tumour growth and spreading, such as proliferation, metabolism and angiogenesis. In vivo, magnesium deficiency, and the resulting inflammation, can trigger both anti-and pro-tumour effects. Recent experimental evidence indicates that altered expression of the transient receptor potential melastatin, type 7 (TRPM7) epithelial magnesium channel is a frequent finding in cancer cells and human tumour tissues, and correlates with cell proliferation and/or migration. We review the role of TRPM7 in tumour development, with particular regard to its channelling function mediating both Ca 2+ and Mg 2+ influx, as well as its kinase activity, likely regulating actomyosin contractility. The potential diagnostic and therapeutic applications based on TRPM7 detection and inhibition, are also discussed.
Magnesium homeostasis in colon carcinoma LoVo cells sensitive or resistant to doxorubicin
Scientific Reports, 2015
Neoplastic cells accumulate magnesium, an event which provides selective advantages and is frequently associated with TRPM7overexpression. Little is known about magnesium homeostasis in drug-resistant cancer cells. Therefore, we used the colon cancer LoVo cell model and compared doxorubicin-resistant to sensitive cells. In resistant cells the concentration of total magnesium is higher while its influx capacity is lower than in sensitive cells. Accordingly, resistant cells express lower amounts of the TRPM6 and 7, both involved in magnesium transport. While decreased TRPM6 levels are due to transcriptional regulation, post-transcriptional events are involved in reducing the amounts of TRPM7. Indeed, the calpain inhibitor calpeptin markedly increases the levels of TRPM7 in resistant cells. In doxorubicin-sensitive cells, silencing TRPM7 shifts the phenotype to one more similar to resistant cells, since in these cells silencing TRPM7 significantly decreases the influx of magnesium, inc...
TRPM7 involvement in cancer: a potential prognostic factor
Magnesium research : official organ of the International Society for the Development of Research on Magnesium
Calcium (Ca(2+)) and magnesium (Mg(2+)) are important metal elements that regulate a variety of cellular processes such as proliferation, migration, and apoptosis, in cancer cells. Among the ionic channels mediating intracellular entry, the transient receptor potential melastatin type 7 (TRPM7) channel is of particular interest, it being a non-selective, cationic channel mediating both Ca(2+) and Mg(2+) influx. TRPM7 is highly expressed in a number of human cancer tissues and cell lines. In this review, we summarise current knowledge on the physiological role of the dual function TRPM7 chanzyme, the potential application of TRPM7 as a diagnostic and prognostic marker of cancer progression with respect to clinical and pathological characteristics, and the molecular mechanisms implicated in cancerogenesis that specifically involve Ca(2+) and Mg(2+) influx through TRPM7 or kinase activity and interaction with cytoskeletal proteins.
Scientific reports, 2017
The processes leading to anticancer drug resistance are not completely unraveled. To get insights into the underlying mechanisms, we compared colon carcinoma cells sensitive to doxorubicin with their resistant counterpart. We found that resistant cells are growth retarded, and show staminal and ultrastructural features profoundly different from sensitive cells. The resistant phenotype is accompanied by the upregulation of the magnesium transporter MagT1 and the downregulation of the ion channel kinase TRPM7. We demonstrate that the different amounts of TRPM7 and MagT1 account for the different proliferation rate of sensitive and resistant colon carcinoma cells. It remains to be verified whether they are also involved in the control of other "staminal" traits.
Journal of Biological Chemistry, 2011
Background: TRPM7 channels are key regulators of cell growth and proliferation. Results: A natural compound from a Hawaiian soft coral blocks TRPM7 currents and inhibits proliferation. Conclusion: Waixenicin A represents the first potent and relatively specific inhibitor of TRPM7 ion channels. Significance: Waixenicin A or structural analogs may have cancer-specific therapeutic potential. . The abbreviations used are: TRPM, transient receptor potential melastatin; CRAC, Ca 2ϩ -release activated Ca 2ϩ current; RBL, rat basophilic leukemia; pA, picoAmpere; pF, picoFarad.
Magnesium-Induced Cell Survival Is Dependent on TRPM7 Expression and Function
Molecular Neurobiology
Mg 2+ homeostasis is essential for cell survival and the loss of this regulation has been associated with many neurodegenerative diseases, including loss of dopaminergic neurons. Although the neurotoxin-mediated loss of dopaminergic neurons in Parkinson disease models is extensively studied, the ion channel(s) that regulate Mg 2+ homeostasis and thus could prevent neuronal cell death is not yet identified. Here, we show that TRPM7 (transient receptor potential melastatin 7) is involved in regulating Mg 2+ homeostasis in dopaminergic cells. Importantly, transient loss of TRPM7 decreased intracellular Mg 2+ levels and decreased dopaminergic cells/neurons survival. We provide further evidence that both increases in extracellular Mg 2+ or transiently increasing TRPM7 levels protected dopaminergic SH-SY5Y cells against neurotoxin-mediated cell death. Neurotoxin treatment significantly decreased TRPM7 levels in both SH-SY5Y cells and the substantia nigra pars compacta region of mice, along with a decrease in Mg 2+ influx. Moreover, Mg 2+ supplementation showed a concentration-dependent decrease in caspase-3 activity, an increase in cell survival, restored mitochondrial membrane potential, and increase TRPM7 levels in neurotoxin-treated cells. In contrast, transient silencing of TRPM7 inhibited the positive effect of Mg 2+ supplementation in protecting against neurotoxins. Whereas, TRPM7 overexpression not only maintained Mg 2+ homeostasis but also inhibited caspase 3 activity that induced cell survival. Overall, these results suggest a significant role of TRPM7 channels in Mg 2+ homeostasis and the survival of neurotoxininduced loss of dopaminergic cells.
TRPM7 is essential for Mg2+ homeostasis in mammals
Nature Communications, 2010
mg 2 + is the second-most abundant cation in animal cells and is an essential cofactor in numerous enzymatic reactions. The molecular mechanisms controlling mg 2 + balance in the organism are not well understood. In this study, we report identification of TRPm7, a bifunctional protein containing a protein kinase fused to an ion channel, as a key regulator of whole body mg 2 + homeostasis in mammals. We generated TRPm7-deficient mice with the deletion of the kinase domain. Homozygous TRPm7 ∆kinase mice demonstrated early embryonic lethality, whereas heterozygous mice were viable, but developed signs of hypomagnesaemia and revealed a defect in intestinal mg 2 + absorption. Cells derived from heterozygous TRPm7 ∆kinase mice demonstrated reduced TRPm7 currents that had increased sensitivity to the inhibition by mg 2 + . Embryonic stem cells lacking TRPm7 kinase domain displayed a proliferation arrest phenotype that can be rescued by mg 2 + supplementation. our results demonstrate that TRPm7 is essential for the control of cellular and whole body mg 2 + homeostasis.
Relationship between low magnesium status and TRPM6 expression in the kidney and large intestine
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2008
The body maintains Mg2+homeostasis by renal and intestinal (re)absorption. However, the molecular mechanisms that mediate transepithelial Mg2+transport are largely unknown. Transient receptor potential melastatin 6 (TRPM6) was recently identified and shown to function in active epithelial Mg2+transport in intestine and kidney. To define the relationship between Mg2+status and TRPM6 expression, we used two models of hypomagnesemia: 1) C57BL/6J mice fed a mildly or severely Mg2+-deficient diet, and 2) mice selected for either low (MgL) or high (MgH) erythrocyte and plasma Mg2+status. In addition, the mice were subjected to a severely Mg2+-deficient diet. Our results show that C57BL/6J mice fed a severely Mg2+-deficient diet developed hypomagnesemia and hypomagnesuria and showed increased TRPM6 expression in kidney and intestine. When fed a Mg2+-adequate diet, MgL mice presented hypomagnesemia and hypermagnesuria, and lower kidney and intestinal TRPM6 expression, compared with MgH mice...
Cellular and Molecular Life Sciences Cmls, 2014
The channel kinases TRPM6 and TRPM7 are both members of the melastatin related transient receptor potential (TRPM) subfamily of ion channels and the only known fusions of an ion channel pore with a kinase domain. TRPM6 and TRPM7 form functional, tetrameric channel complexes at the plasma membrane by heteromerization. TRPM6 was previously shown to crossphosphorylate TRPM7 on threonine residues, but not vice versa. Genetic studies demonstrated that TRPM6 and TRPM7 fulfill non-redundant functions, and that each channel contributes uniquely to the regulation of Mg 2+ homeostasis. Although there are indications that TRPM6 and TRPM7 can influence each other's cellular distribution and activity, little is known about the functional relationship between these two channel-kinases.