Magnesium transporter protein solute carrier family 41 member 1 suppresses human pancreatic ductal adenocarcinoma through magnesium-dependent Akt/mTOR inhibition and bax-associated mitochondrial apoptosis

Xie, Jing; Cheng, Chien-Shan; Zhu, Xiao Jun; Ye, Shen; Li, Song; Chen, Hao; Chen, Zhe; Liu, Lu Ming; Meng, Zhi Qiang

doi:10.18632/aging.101940

Cited by 28 publications

(23 citation statements)

References 48 publications

(49 reference statements)

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“…SLC17A7, SLC25A5, SLC35A2 are series of transporters expressed in organ and tissue of the digestive tract involved in the uptake of a small molecule ( Figure 8 a) [ 55 , 56 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

Unsupervised subtyping and methylation landscape of pancreatic ductal adenocarcinoma

Roy¹,

Singh²,

Gupta

2021

Heliyon

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Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive form of pancreatic cancer that typically manifests itself at an advanced stage and does not respond to most treatment modalities. The survival rate of a PDAC patient is less than 5%, with a median survival of just a couple of months. A better understanding of the molecular pathology of PDAC is needed to guide research for the development of better clinical treatment modalities for PDAC patients. Gene expression studies performed to date have identified different subtypes of PDAC with prognostic and clinical relevance. Subtypes identified to date are highly heterogeneous since pancreatic cancer is heterogeneous cancer. Tumor microenvironment and stroma constitute a major chunk of PDAC and contribute to the heterogeneity. Better subtyping methods are need of the hour for better prognosis and classification of PDAC for future personalized treatment. In this work, we have performed an integrated analysis of DNA methylation and gene expression datasets to provide better mechanistic and molecular insights into Pancreatic cancers, especially PDAC. The use of varied and diverse datasets has provided valuable insights into different cancer types and can play an integral role in revealing the complex nature of underlying biological mechanisms. We performed subtyping of TCGA-PAAD gene expression and methylation datasets into different subtypes using state-of-the-art normalization methods and unsupervised clustering methods that reveal latent hidden factors, leading to additional insights for subtyping. Differential expression and differential methylation were performed for each of the subtypes obtained from clustering. Our analysis gave a consensus of five cluster solution with relevant pathways like MAPK, MET. The five subtypes corresponded to the tumor and stromal subtypes. This analysis helps in distinguishing and identifying different subtypes based on enriched putative genes. These results help propose novel experimentally-verifiable PDAC subtyping and demonstrate that using varied data sets and integrated methods can contribute to disease prognostication and precision medicine in PDAC treatment.

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“…SLC17A7, SLC25A5, SLC35A2 are series of transporters expressed in organ and tissue of the digestive tract involved in the uptake of a small molecule ( Figure 8 a) [ 55 , 56 , 57 ].…”

Section: Resultsmentioning

confidence: 99%

Unsupervised subtyping and methylation landscape of pancreatic ductal adenocarcinoma

Roy¹,

Singh²,

Gupta

2021

Heliyon

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“…The mTOR pathway is implicated in the regulation of cellular metabolism and proliferation [36]. In pancreatic cancer cells, overexpression of SLC41A1, a membrane protein for Mg 2+ extrusion [32], and the resulting low [Mg 2+ ] i , inhibited the Akt/mTOR pathway and cancer proliferation [44]. In cultured hippocampal neurons, [Mg 2+ ] i within the physiological concentration range is correlated with mTOR activity [23].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Mg2+ Extrusion Attenuates Glutamate Excitotoxicity in Cultured Rat Hippocampal Neurons

et al. 2020

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Magnesium plays important roles in the nervous system. An increase in the Mg2+ concentration in cerebrospinal fluid enhances neural functions, while Mg2+ deficiency is implicated in neuronal diseases in the central nervous system. We have previously demonstrated that high concentrations of glutamate induce excitotoxicity and elicit a transient increase in the intracellular concentration of Mg2+ due to the release of Mg2+ from mitochondria, followed by a decrease to below steady-state levels. Since Mg2+ deficiency is involved in neuronal diseases, this decrease presumably affects neuronal survival under excitotoxic conditions. However, the mechanism of the Mg2+ decrease and its effect on the excitotoxicity process have not been elucidated. In this study, we demonstrated that inhibitors of Mg2+ extrusion, quinidine and amiloride, attenuated glutamate excitotoxicity in cultured rat hippocampal neurons. A toxic concentration of glutamate induced both Mg2+ release from mitochondria and Mg2+ extrusion from cytosol, and both quinidine and amiloride suppressed only the extrusion. This resulted in the maintenance of a higher Mg2+ concentration in the cytosol than under steady-state conditions during the ten-minute exposure to glutamate. These inhibitors also attenuated the glutamate-induced depression of cellular energy metabolism. Our data indicate the importance of Mg2+ regulation in neuronal survival under excitotoxicity.

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“…TRPM7 expression correlates with tumor size, grade, and a high expression of this protein associates with a poor prognosis in patients [ 75 , 76 ]. On the other hand, SLC41A1 protein and mRNA were downregulated in PDAC patients compared to normal adjacent tissues, using quantitative real time-PCR (qRT-PCR), IHC, and in silico studies [ 78 ]. SLC41A1 expression is inversely correlated with tumor grade and was positively associated with a better outcome for patients [ 78 ].…”

Section: Expression Of Mg 2+ Transporters In DImentioning

confidence: 99%

“…Xie and collaborators were able to show a direct relationship between expression of the SLC41A1 transporter and activation of the AKT/mTOR pathway [ 78 ]. SLC41A1 mediates both Mg 2+ uptake and extrusion [ 102 ].…”

Section: Mg 2+ -Regulated Signaling Pathways Inmentioning

confidence: 99%

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Mg2+ Transporters in Digestive Cancers

et al. 2021

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Despite magnesium (Mg2+) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg2+ homeostasis is regulated by Mg2+ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg2+ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg2+ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg2+ transporters’ expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg2+ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.

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Magnesium transporter protein solute carrier family 41 member 1 suppresses human pancreatic ductal adenocarcinoma through magnesium-dependent Akt/mTOR inhibition and bax-associated mitochondrial apoptosis

Cited by 28 publications

References 48 publications

Unsupervised subtyping and methylation landscape of pancreatic ductal adenocarcinoma

Unsupervised subtyping and methylation landscape of pancreatic ductal adenocarcinoma

Inhibition of Mg2+ Extrusion Attenuates Glutamate Excitotoxicity in Cultured Rat Hippocampal Neurons

Mg2+ Transporters in Digestive Cancers

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