scholarly journals TRPM8 facilitates proliferation and immune evasion of esophageal cancer cells

2019 ◽  
Vol 39 (10) ◽  
Author(s):  
Xinyan Lan ◽  
Jun Zhao ◽  
Chunjing Song ◽  
Qiuxiang Yuan ◽  
Xiaojun Liu
Keyword(s):  
T Cells ◽  
Esophageal Cancer ◽  
Cancer Cells ◽  
Immune Evasion ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Activated T Cells ◽  
Transient Receptor Potential Melastatin ◽  
Esophageal Cancer Cells ◽  
Trpm Channels

Abstract Esophageal cancer is seen with increasing incidence, but the underlying mechanism of esophageal cancer is still unknown. Transient receptor potential melastatin (TRPM) is non-selective cation channels. It has been verified that TRPM channels play crucial roles in development and progression of multiple tumors. Increasing studies have shown that TRPM8, a member of TRPM channels, promotes growth of tumors. However, it is still unclear whether TRPM8 has biological effect on esophageal cancer. In the current work, we found that TRPM8 was overexpressed in esophageal cancer samples and cell lines. Further investigation revealed that TRPM8 promoted proliferation of esophageal cancer cells. Next, the co-incubation assay including EC109 cells and CD8+ T cells revealed that TRPM8 overexpression and TRPM8 agonist reduced the cytotoxic effect of CD8+ T cell on esophageal cancer cells. Finally, we explored the mechanism and found that calcineurin-nuclear factor of activated T cells 3 (NFATc3) pathway contributed to the expression of programmed death ligand 1 (PD-L1) induced by TRPM8 overexpression and TRPM8 agonist, which might lead to immune evasion of esophageal cancer cells. These findings uncovered the crucial role of TRPM8 in the pathogenesis of esophageal cancer.

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

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 131 ◽  
Author(s):  
Hengrui Liu ◽  
James P. Dilger ◽  
Jun Lin
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Divalent Cation ◽  
Breast Cancer Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

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.

Epigenetic modulation combined with PD-1/PD-L1 blockade enhances immunotherapy based on MAGE-A11 antigen-specific CD8+T cells against esophageal carcinoma

2020 ◽  
Vol 41 (7) ◽  
pp. 894-903
Author(s):  
Yunyan Wu ◽  
Meixiang Sang ◽  
Fei Liu ◽  
Jiandong Zhang ◽  
Weijing Li ◽  
...  
Keyword(s):  
T Cells ◽  
Esophageal Cancer ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cd8 T Cells ◽  
Dna Methyltransferase ◽  
Tumor Cell Lines ◽  
Epigenetic Modulation ◽  
Esophageal Cancer Cells

Abstract Cancer testis antigens (CTAs) are promising targets for T cell-based immunotherapy and studies have shown that certain CT genes are epigenetically depressed in cancer cells through DNA demethylation. Melanoma-associated antigen A11 (MAGE-A11) is a CTA that is frequently expressed in esophageal cancer and is correlated with a poor esophageal cancer prognosis. Consequently, MAGE-A11 is a potential immunotherapy target. In this study, we evaluated MAGE-A11 expression in esophageal cancer cells and found that it was downregulated in several tumor cell lines, which restricted the effect of immunotherapy. Additionally, the specific recognition and lytic potential of cytotoxic T lymphocytes (CTLs) derived from the MAGE-A11 was determined. Specific CTLs could kill esophageal cancer cells expressing MAGE-A11 but rarely lysed MAGE-A11-negative tumor cells. Therefore, induction of MAGE-A11 expression is critical for CTLs recognition and lysis of esophageal cancer cells. Treatment with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine increased MAGE-A11 expression in esophageal cancer cells and subsequently enhanced the cytotoxicity of MAGE-A11-specific CD8+T cells against cancer cell lines. Furthermore, we found that PD-L1 expression in esophageal cancer cells affected the antitumor function of CTLs. programmed death-1 (PD-1)/PD-L1 blockade could increase the specific CTL-induced lysis of HLA-A2+/MAGE-A11+ tumor cell lines treated with 5-aza-2′-deoxycytidine. These findings indicate that the treatment of tumor cells with the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine augments MAGE-A11 expression in esophageal cancer cells. The combination of epigenetic modulation by 5-aza-2′-deoxycytidine and PD-1/PD-L1 blockade may be useful for T cell-based immunotherapy against esophageal cancer.

scholarly journals Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy

2020 ◽  
Vol 10 ◽  
Author(s):  
Yuan Huang ◽  
Shi Li ◽  
Zhenhua Jia ◽  
Weiwei Zhao ◽  
Cefan Zhou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Ampk Activity ◽  
Transient Receptor ◽  
And Migration ◽  
Proliferation And Migration

The calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is closely regulated by AMP-activated protein kinase (AMPK) and plays an important role in tumor growth by generating nutrients through degradation of intracellular structures. Additionally, AMPK activity is regulated by intracellular Ca2+ concentration. Considering that TRPM8 is a non-selective Ca2+-permeable cation channel and plays a key role in calcium homoeostasis, we hypothesized that TRPM8 may control AMPK activity thus modulating cellular autophagy to regulate the proliferation and migration of breast cancer cells. In this study, overexpression of TRPM8 enhanced the level of basal autophagy, whereas TRPM8 knockdown reduced the level of basal autophagy in several types of mammalian cancer cells. Moreover, the activity of the TRPM8 channel modulated the level of basal autophagy. The mechanism of regulation of autophagy by TRPM8 involves autophagy-associated signaling pathways for activation of AMPK and ULK1 and phagophore formation. Impaired AMPK abolished TRPM8-dependent regulation of autophagy. TRPM8 interacts with AMPK in a protein complex, and cytoplasmic C-terminus of TRPM8 mediates the TRPM8–AMPK interaction. Finally, basal autophagy mediates the regulatory effects of TRPM8 on the proliferation and migration of breast cancer cells. Thus, this study identifies TRPM8 as a novel regulator of basal autophagy in cancer cells acting by interacting with AMPK, which in turn activates AMPK to activate ULK1 in a coordinated cascade of TRPM8-mediated breast cancer progression.

scholarly journals TRPM channels mediate learned pathogen avoidance following intestinal distention

2020 ◽  
Author(s):  
Adam Filipowicz ◽  
Alejandro Aballay
Keyword(s):  
Transient Receptor Potential ◽  
Bacterial Colonization ◽  
Anterior Part ◽  
Receptor Potential ◽  
Aversive Learning ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Pathogen Avoidance ◽  
Dependent Pathway ◽  
Trpm Channels

Upon exposure to harmful microorganisms, hosts engage in protective molecular and behavioral immune responses, both of which are ultimately regulated by the nervous system. Using the nematode Caenorhabditis elegans, we show that ingestion of E. faecalis leads to a fast pathogen avoidance behavior that results in aversive learning. We have identified multiple sensory mechanisms involved in the regulation of avoidance of E. faecalis, including the GPCR NPR-1-dependent oxygen-sensing pathway, an ASE neuron-dependent pathway, and an AWB and AWC neuron-dependent pathway. Colonization of the anterior part of the intestine by E. faecalis leads to AWB and AWC mediated olfactory aversive learning. Finally, two transient receptor potential melastatin (TRPM) channels, GON-2 and GTL-2, mediate this newly described rapid pathogen avoidance. These results suggest a mechanism by which TRPM channels may sense the intestinal distension caused by bacterial colonization to elicit pathogen avoidance and aversive learning by detecting changes in host physiology.

scholarly journals Transient receptor potential melastatin 4 channel contributes to migration of androgen-insensitive prostate cancer cells

Oncotarget ◽  
2015 ◽  
Vol 6 (39) ◽  
pp. 41783-41793 ◽  
Author(s):  
Christian Holzmann ◽  
Sven Kappel ◽  
Tatiana Kilch ◽  
Marcus Martin Jochum ◽  
Sabine Katharina Urban ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Prostate Cancer Cells ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Subunit interaction in channel assembly and functional regulation of transient receptor potential melastatin (TRPM) channels

2007 ◽  
Vol 35 (1) ◽  
pp. 86-88 ◽  
Author(s):  
L.-H. Jiang
Keyword(s):  
Transient Receptor Potential ◽  
Current Knowledge ◽  
Receptor Potential ◽  
Subunit Interaction ◽  
Transient Receptor Potential Melastatin ◽  
Functional Regulation ◽  
Transient Receptor ◽  
Channel Assembly ◽  
Translational Mechanisms ◽  
Trpm Channels

Functional TRPM (transient receptor potential melastatin) ion channels are multimers, thought to be tetramers. Subunit interaction is the prerequisite step in channel assembly, and the specificity of subunit interaction is crucial in assembling channels with distinct functional properties. In addition, expression of short non-functional subunits and their interaction with full-length subunits serve as one of the post-translational mechanisms regulating the channel activity. This paper aims to provide an overview of the current knowledge of TRPM subunit interactions and their roles in assembly and functional regulation of the TRPM channels.

scholarly journals PRMT5 promotes symmetric dimethylation of RNA processing proteins and modulates activated T cell alternative splicing and Ca2+/NFAT signaling

2021 ◽  
Author(s):  
Shouvonik Sengupta ◽  
Kelsi O. West ◽  
Shridhar Sanghvi ◽  
Georgios Laliotis ◽  
Laura M. Agosto ◽  
...  
Keyword(s):  
T Cells ◽  
Alternative Splicing ◽  
T Cell ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Major Type ◽  
Activated T Cells ◽  
Th Cell ◽  
Activated T Cell ◽  
Transient Receptor

AbstractProtein Arginine Methyltransferase (PRMT) 5 is the major type 2 methyltransferase catalyzing symmetric dimethylation (SDM) of arginine. PRMT5 inhibition or deletion in CD4 Th cells reduces TcR engagement-induced IL-2 production and Th cell expansion and confers protection against experimental autoimmune encephalomyelitis (EAE), the animal model of Multiple Sclerosis. However, the mechanisms by which PRMT5 modulates T helper (Th) cell proliferation are still not completely understood and neither are the methylation targets in T cells. In this manuscript, we uncover the role of PRMT5 on alternative splicing (AS) in activated T cells and identify several targets of PRMT5 SDM involved in splicing. In addition, we find a possible link between PRMT5 mediated AS of Trpm4 (Transient Receptor Potential Cation Channel Subfamily M Member 4) and TcR/NFAT signaling/IL-2 production. This understanding may guide development of drugs targeting these processes to benefit patients with T cell-mediated diseases.

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