scholarly journals TRPM8-androgen receptor association within lipid rafts promotes prostate cancer cell migration

2019 ◽  
Vol 10 (9) ◽  
Author(s):  
Guillaume P. Grolez ◽  
Dmitri V. Gordiendko ◽  
Manon Clarisse ◽  
Mehdi Hammadi ◽  
Emilie Desruelles ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Migration ◽  
Androgen Receptor ◽  
Lipid Rafts ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Underlying Mechanism ◽  
Trpm8 Channel ◽  
Transient Receptor Potential Melastatin ◽  
Novel Therapeutic Strategies

Abstract In prostate carcinogenesis, androgens are known to control the expression of the transient receptor potential melastatin 8 (TRPM8) protein via activation of androgen receptor (AR). Overexpression and/or activity of TRPM8 channel was shown to suppress prostate cancer (PCa) cell migration. Here we report that at certain concentrations androgens facilitate PCa cell migration. We show that underlying mechanism is inhibition of TRPM8 by activated AR which interacts with the channel within lipid rafts microdomains of the plasma membrane. Thus, our study has identified an additional nongenomic mechanism of the TRPM8 channel regulation by androgens that should be taken into account upon the development of novel therapeutic strategies.

scholarly journals Therapeutic potential of TRPM8 antagonists in prostate cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marzia Di Donato ◽  
Carmine Ostacolo ◽  
Pia Giovannelli ◽  
Veronica Di Sarno ◽  
Isabel M. Gomez Monterrey ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Transient Receptor Potential ◽  
Prostate Cancer Cell ◽  
Receptor Potential ◽  
Prostate Cancer Cells ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

AbstractTransient receptor potential melastatin-8 (TRPM8) represents an emerging target in prostate cancer, although its mechanism of action remains unclear. Here, we have characterized and investigated the effects of TRPM8 modulators in prostate cancer aggressiveness disclosing the molecular mechanism underlying their biological activity. Patch-clamp and calcium fluorometric assays were used to characterize the synthesized compounds. Androgen-stimulated prostate cancer-derived cells were challenged with the compounds and the DNA synthesis was investigated in a preliminary screening. The most effective compounds were then employed to inhibit the pro-metastatic behavior of in various PC-derived cells, at different degree of malignancy. The effect of the compounds was then assayed in prostate cancer cell-derived 3D model and the molecular targets of selected compounds were lastly identified using transcriptional and non-transcriptional reporter assays. TRPM8 antagonists inhibit the androgen-dependent prostate cancer cell proliferation, migration and invasiveness. They are highly effective in reverting the androgen-induced increase in prostate cancer cell spheroid size. The compounds also revert the proliferation of castrate-resistant prostate cancer cells, provided they express the androgen receptor. In contrast, no effects were recorded in prostate cancer cells devoid of the receptor. Selected antagonists interfere in non-genomic androgen action and abolish the androgen-induced androgen receptor/TRPM8 complex assembly as well as the increase in intracellular calcium levels in prostate cancer cells. Our results shed light in the processes controlling prostate cancer progression and make the transient receptor potential melastatin-8 as a ‘druggable’ target in the androgen receptor-expressing prostate cancers.

scholarly journals TRPM4 in Cancer—A New Potential Drug Target

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 229
Author(s):  
Anna Borgström ◽  
Christine Peinelt ◽  
Paulina Stokłosa
Keyword(s):  
Anticancer Drug ◽  
Drug Target ◽  
Transient Receptor Potential ◽  
Human Cancer ◽  
Receptor Potential ◽  
B Cell Lymphoma ◽  
Underlying Mechanism ◽  
Monovalent Cation ◽  
Transient Receptor Potential Melastatin ◽  
And Migration

Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

scholarly journals Regulation of Activity of Transient Receptor Potential Melastatin 8 (TRPM8) Channel by Its Short Isoforms

2011 ◽  
Vol 287 (5) ◽  
pp. 2948-2962 ◽  
Author(s):  
Gabriel Bidaux ◽  
Benjamin Beck ◽  
Alexander Zholos ◽  
Dmitri Gordienko ◽  
Loic Lemonnier ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Trpm8 Channel ◽  
Short Isoforms ◽  
Transient Receptor Potential Melastatin ◽  
Regulation Of Activity ◽  
Transient Receptor

scholarly journals Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel

Science ◽  
2019 ◽  
Vol 363 (6430) ◽  
pp. eaav9334 ◽  
Author(s):  
Ying Yin ◽  
Son C. Le ◽  
Allen L. Hsu ◽  
Mario J. Borgnia ◽  
Huanghe Yang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Structural Information ◽  
Receptor Potential ◽  
Membrane Lipid ◽  
Structural Basis ◽  
Trpm8 Channel ◽  
Allosteric Coupling ◽  
Transient Receptor Potential Melastatin ◽  
Lipid Sensing ◽  
Transient Receptor

Transient receptor potential melastatin member 8 (TRPM8) is a calcium ion (Ca2+)–permeable cation channel that serves as the primary cold and menthol sensor in humans. Activation of TRPM8 by cooling compounds relies on allosteric actions of agonist and membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), but lack of structural information has thus far precluded a mechanistic understanding of ligand and lipid sensing by TRPM8. Using cryo–electron microscopy, we determined the structures of TRPM8 in complex with the synthetic cooling compound icilin, PIP2, and Ca2+, as well as in complex with the menthol analog WS-12 and PIP2. Our structures reveal the binding sites for cooling agonists and PIP2in TRPM8. Notably, PIP2binds to TRPM8 in two different modes, which illustrate the mechanism of allosteric coupling between PIP2and agonists. This study provides a platform for understanding the molecular mechanism of TRPM8 activation by cooling agents.

scholarly journals Transient Receptor Potential Melastatin 4 (TRPM4) Contributes to High Salt Diet-Mediated Early-Stage Endothelial Injury

2017 ◽  
Vol 41 (2) ◽  
pp. 835-848 ◽  
Author(s):  
Xiao-Qing Ding ◽  
Tao Ban ◽  
Zeng-Yan Liu ◽  
Jie Lou ◽  
Liang-Liang Tang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Cell Migration ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
High Salt Diet ◽  
Salt Diet ◽  
Transient Receptor Potential Melastatin ◽  
Intracellular Ros ◽  
Transient Receptor

Background/Aims: The present study investigated whether the transient receptor potential melastatin 4 (TRPM4) channel plays a role in high salt diet (HSD)-induced endothelial injuries. Methods: Western blotting and immunofluorescence were used to examine TRPM4 expression in the mesenteric endothelium of Dahl salt-sensitive (SS) rats fed a HSD. The MTT, TUNEL, and transwell assays were used to evaluate the cell viability, cell apoptosis, and cell migration, respectively, of human umbilical vein endothelial cells (HUVECs). Enzyme-linked immunosorbent assays were used to determine the concentrations of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), and E-selectin. Carboxy-H2DCFDA, a membrane-permeable reactive oxygen species (ROS)-sensitive fluorescent probe, was used to detect intracellular ROS levels. Results: TRPM4 was mainly expressed near the plasma membrane of mesenteric artery endothelial cells, and its expression level increased in SS hypertensive rats fed a HSD. Its protein expression was significantly upregulated upon treatment with exogenous hydrogen peroxide (H2O2) and aldosterone in cultured HUVECs. Cell viability decreased upon treatment with both agents in a concentration-dependent manner, which could be partially reversed by 9-phenanthrol, a specific TRPM4 inhibitor. Exogenous H2O2 induced apoptosis, enhanced cell migration, and increased the release of adhesion molecules, including ICAM-1, VCAM-1, and E-selectin, all of which were significantly attenuated upon treatment with 9-phenanthrol. Aldosterone and H2O2 induced the accumulation of intracellular ROS, which was significantly inhibited by 9-phenanthrol, suggesting that oxidative stress is one of the mechanisms underlying aldosterone-induced endothelial injury. Conclusions: Given the fact that oxidative stress and high levels of circulating aldosterone are present in hypertensive patients, we suggest that the upregulation of TRPM4 in the vascular endothelium may be involved in endothelial injuries caused by these stimuli.

TRPM8 activation suppresses cellular viability in human melanoma

2008 ◽  
Vol 295 (2) ◽  
pp. C296-C301 ◽  
Author(s):  
Hisao Yamamura ◽  
Shinya Ugawa ◽  
Takashi Ueda ◽  
Akimichi Morita ◽  
Shoichi Shimada
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Specific Gene ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Trpm8 Channel ◽  
Transient Receptor Potential Melastatin ◽  
Inward Currents

The transient receptor potential melastatin subfamily (TRPM), which is a mammalian homologue of cell death-regulated genes in Caenorhabditis elegans and Drosophila, has potential roles in the process of the cell cycle and regulation of Ca2+ signaling. Among this subfamily, TRPM8 (also known as Trp-p8) is a Ca2+-permeable channel that was originally identified as a prostate-specific gene upregulated in tumors. Here we showed that the TRPM8 channel was expressed in human melanoma G-361 cells, and activation of the channel produced sustainable Ca2+ influx. The application of menthol, an agonist for TRPM8 channel, elevated cytosolic Ca2+ concentration in a concentration-dependent manner with an EC50 value of 286 μM in melanoma cells. Menthol-induced responses were significantly abolished by the removal of external Ca2+. Moreover, inward currents at a holding potential of −60 mV in melanoma cells were markedly potentiated by the addition of 300 μM menthol. The most striking finding was that the viability of melanoma cells was dose-dependently depressed in the presence of menthol. These results reveal that a functional TRPM8 protein is expressed in human melanoma cells to involve the mechanism underlying tumor progression via the Ca2+ handling pathway, providing us with a novel target of drug development for malignant melanoma.

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
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