scholarly journals Transient Receptor Potential Channel Expression Signatures in Tumor-Derived Endothelial Cells: Functional Roles in Prostate Cancer Angiogenesis

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 956 ◽  
Author(s):  
Michela Bernardini ◽  
Alessia Brossa ◽  
Giorgia Chinigo ◽  
Guillaume P. Grolez ◽  
Giulia Trimaglio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Angiogenic Factor ◽  
Renal Tumors ◽  
Transient Receptor

Background: Transient receptor potential (TRP) channels control multiple processes involved in cancer progression by modulating cell proliferation, survival, invasion and intravasation, as well as, endothelial cell (EC) biology and tumor angiogenesis. Nonetheless, a complete TRP expression signature in tumor vessels, including in prostate cancer (PCa), is still lacking. Methods: In the present study, we profiled by qPCR the expression of all TRP channels in human prostate tumor-derived ECs (TECs) in comparison with TECs from breast and renal tumors. We further functionally characterized the role of the ‘prostate-associated’ channels in proliferation, sprout formation and elongation, directed motility guiding, as well as in vitro and in vivo morphogenesis and angiogenesis. Results: We identified three ‘prostate-associated’ genes whose expression is upregulated in prostate TECs: TRPV2 as a positive modulator of TEC proliferation, TRPC3 as an endothelial PCa cell attraction factor and TRPA1 as a critical TEC angiogenic factor in vitro and in vivo. Conclusions: We provide here the full TRP signature of PCa vascularization among which three play a profound effect on EC biology. These results contribute to explain the aggressive phenotype previously observed in PTEC and provide new putative therapeutic targets.

scholarly journals Cross-kingdom regulation of tRNAs/tRFs derived from Chinese yew

2019 ◽  
Author(s):  
Kai-Yue Cao ◽  
Tong-Meng Yan ◽  
Ji-Zhou Zhang ◽  
Ting-Fung Chan ◽  
Jie Li ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Target Genes ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Chemical Constituent ◽  
Biological Studies ◽  
Transient Receptor ◽  
Pharmacologically Active

Plants containing countless chemical constituent have benefited mankind since the origin of life. Although secondary metabolites in plants, such as morphine, artemisinin and taxol, have been developed as therapeutic drugs for clinical therapy, few study focuses on the pharmacological activities of plant small RNAs with function of cross-kingdom regulations. Yew is widely considered as a “superstar” plant due to the discovery of paclitaxel, or taxol, which is a well-known natural drug for the treatment of multiple types of cancer1. Here we show the surprising finding that an RNA fragment, named tRF-T11, derived from tRNAHis(GUG) of Chinese yew strongly suppressed human ovarian cancer progression. In A2780 cells, tRF-T11 mimic (a double-stranded RNA with tRF-T11 as antisense chain) exhibited potent cytotoxicity comparable to that of taxol, but no significant cytotoxicity to normal ovarian surface epithelial cells. Moreover, the cytotoxicity of tRF-T11 mimic is 80-fold stronger than that of taxol in taxol-resistant A2780 cells. Bioinformatic and molecular biological studies revealed that tRF-T11 targets transient receptor potential cation channel subfamily A member 1 (TRPA1) to inhibit its expression levels. In a further in vivo investigation, the growth rate of ovarian tumor xenografts in nude mice was significantly reduced by treatment with tRF-T11 mimic, and the TRPA1 protein expression in tumors treated with tRF-T11 mimic was also down-regulated. Our findings are the first to provide evidence that plant-derived tRFs can regulate the expression of target genes in vitro and in vivo, indicating that they may become as a new source of druggable siRNA. Moreover, this discovery demonstrated a pilot example of an innovative approach for not only identifying pharmacologically-active tRFs from plants, but also for improving the efficiency and possibilities of discovering new drug target.

scholarly journals Novel role of transient receptor potential vanilloid 2 in the regulation of cardiac performance

2014 ◽  
Vol 306 (4) ◽  
pp. H574-H584 ◽  
Author(s):  
Jack Rubinstein ◽  
Valerie M. Lasko ◽  
Sheryl E. Koch ◽  
Vivek P. Singh ◽  
Vinicius Carreira ◽  
...  
Keyword(s):  
Vascular Function ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Wild Type ◽  
Transient Receptor ◽  
Systolic And Diastolic Function ◽  
Myocyte Contractility

Transient receptor potential cation channels have been implicated in the regulation of cardiovascular function, but only recently has our laboratory described the vanilloid-2 subtype (TRPV2) in the cardiomyocyte, though its exact mechanism of action has not yet been established. This study tests the hypothesis that TRPV2 plays an important role in regulating myocyte contractility under physiological conditions. Therefore, we measured cardiac and vascular function in wild-type and TRPV2−/− mice in vitro and in vivo and found that TRPV2 deletion resulted in a decrease in basal systolic and diastolic function without affecting loading conditions or vascular tone. TRPV2 stimulation with probenecid, a relatively selective TRPV2 agonist, caused an increase in both inotropy and lusitropy in wild-type mice that was blunted in TRPV2−/− mice. We examined the mechanism of TRPV2 inotropy/lusitropy in isolated myocytes and found that it modulates Ca2+ transients and sarcoplasmic reticulum Ca2+ loading. We show that the activity of this channel is necessary for normal cardiac function and that there is increased contractility in response to agonism of TRPV2 with probenecid.

scholarly journals Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

2013 ◽  
Vol 304 (4) ◽  
pp. G428-G436 ◽  
Author(s):  
Toru Kono ◽  
Atsushi Kaneko ◽  
Yuji Omiya ◽  
Katsuya Ohbuchi ◽  
Nagisa Ohno ◽  
...  
Keyword(s):  
Blood Flow ◽  
Small Intestine ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Allyl Isothiocyanate ◽  
Antibody Treatment ◽  
Functional Roles ◽  
Transient Receptor

The functional roles of transient receptor potential (TRP) channels in the gastrointestinal tract have garnered considerable attention in recent years. We previously reported that daikenchuto (TU-100), a traditional Japanese herbal medicine, increased intestinal blood flow (IBF) via adrenomedullin (ADM) release from intestinal epithelial (IE) cells (Kono T et al. J Crohns Colitis 4: 161–170, 2010). TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders.

scholarly journals Calcium and TRPV4 promote metastasis by regulating cytoskeleton through the RhoA/ROCK1 pathway in endometrial cancer

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Xingchen Li ◽  
Yuan Cheng ◽  
Zhiqi Wang ◽  
Jingyi Zhou ◽  
Yuanyuan Jia ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cancer Progression ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Biological Significance ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Mechanistic Investigation

AbstractTransient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that has been associated with several types of cancer. However, its biological significance, as well as its related mechanism in endometrial cancer (EC) still remains elusive. In this study, we examined the function of calcium in EC, with a specific focus on TRPV4 and its downstream pathway. We reported here on the findings that a high level of serum ionized calcium was significantly correlated with advanced EC progression, and among all the calcium channels, TRPV4 played an essential role, with high levels of TRPV4 expression associated with cancer progression both in vitro and in vivo. Proteomic and bioinformatics analysis revealed that TRPV4 was involved in cytoskeleton regulation and Rho protein pathway, which regulated EC cell migration. Mechanistic investigation demonstrated that TRPV4 and calcium influx acted on the cytoskeleton via the RhoA/ROCK1 pathway, ending with LIMK/cofilin activation, which had an impact on F-actin and paxillin (PXN) levels. Overall, our findings indicated that ionized serum calcium level was significantly associated with poor outcomes and calcium channel TRPV4 should be targeted to improve therapeutic and preventive strategies in EC.

scholarly journals Transient Receptor Potential Cation Channels in Cancer Therapy

2019 ◽  
Vol 7 (12) ◽  
pp. 108 ◽  
Author(s):  
Giorgio Santoni ◽  
Federica Maggi ◽  
Maria Beatrice Morelli ◽  
Matteo Santoni ◽  
Oliviero Marinelli
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Cancer Cells ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Chemotherapeutic Agents ◽  
Migration And Invasion ◽  
Transient Receptor

In mammals, the transient receptor potential (TRP) channels family consists of six different families, namely TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPA (ankyrin), that are strictly connected with cancer cell proliferation, differentiation, cell death, angiogenesis, migration, and invasion. Changes in TRP channels’ expression and function have been found to regulate cell proliferation and resistance or sensitivity of cancer cells to apoptotic-induced cell death, resulting in cancer-promoting effects or resistance to chemotherapy treatments. This review summarizes the data reported so far on the effect of targeting TRP channels in different types of cancer by using multiple TRP-specific agonists, antagonists alone, or in combination with classic chemotherapeutic agents, microRNA specifically targeting the TRP channels, and so forth, and the in vitro and in vivo feasibility evaluated in experimental models and in cancer patients. Considerable efforts have been made to fight cancer cells, and therapies targeting TRP channels seem to be the most promising strategy. However, more in-depth investigations are required to completely understand the role of TRP channels in cancer in order to design new, more specific, and valuable pharmacological tools.

A role for transient receptor potential ankyrin 1 cation channel (TRPA1) in airway hyper-responsiveness?

2015 ◽  
Vol 93 (3) ◽  
pp. 171-176 ◽  
Author(s):  
Aruni Jha ◽  
Pawan Sharma ◽  
Vidyanand Anaparti ◽  
Min H. Ryu ◽  
Andrew J. Halayko
Keyword(s):  
Airway Inflammation ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Cation Channel ◽  
Chronic Obstructive ◽  
Airway Narrowing ◽  
Airway Caliber ◽  
Transient Receptor

Airway smooth muscle (ASM) contraction controls the airway caliber. Airway narrowing is exaggerated in obstructive lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). The mechanism by which ASM tone is dysregulated in disease is not clearly understood. Recent research on ion channels, particularly transient receptor potential cation channel, subfamily A, member 1 (TRPA1), is uncovering new understanding of altered airway function. TRPA1, a member of the TRP channel superfamily, is a chemo-sensitive cation channel that can be activated by a variety of external and internal stimuli, leading to the influx of Ca2+. Functional TRPA1 channels have been identified in neuronal and non-neuronal tissues of the lung, including ASM. In the airways, these channels can regulate the release of mediators that are markers of airway inflammation in asthma and COPD. For, example, TRPA1 controls cigarette-smoke-induced inflammatory mediator release and Ca2+ mobilization in vitro and in vivo, a response tied to disease pathology in COPD. Recent work has revealed that pharmacological or genetic inhibition of TRPA1 inhibits the allergen-induced airway inflammation in vitro and airway hyper-responsiveness (AHR) in vivo. Collectively, it appears that TRPA1 channels may be determinants of ASM contractility and local inflammation control, positioning them as part of novel mechanisms that control (patho)physiological function of airways and ASM.

Transient receptor potential ankyrin 1 (TRPA1) ion channel in the pathophysiology of peripheral diabetic neuropathy

2013 ◽  
Vol 4 (3) ◽  
pp. 129-136 ◽  
Author(s):  
Ari Koivisto ◽  
Antti Pertovaara
Keyword(s):  
Diabetic Neuropathy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Axon Reflex ◽  
Pain Hypersensitivity ◽  
Peripheral Diabetic Neuropathy ◽  
Transient Receptor ◽  
Sustained Activation

AbstractBackgroundTransient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel permeable to calcium that is expressed on pain-mediating primary afferent nerve fibers. Here we review recent experimental evidence supporting the hypothesis that activation of the TRPA1 channel by reactive compounds generated in diabetes mellitus, such as 4-hydroxynonenal and methylglyoxal, exerts an important role in the pathophysiology of peripheral diabetic neuropathy (PDN). The hypothesis includes development of the early diabetic pain hypersensitivity and the later loss of cutaneous nerve endings of pain fibers and their dysfunction, which are hallmarks of peripheral diabetic neuropathy (PDN).Methods The evidence for a role of the TRPA1 channel in PDN consists of in vitro patch clamp and calcium imaging data and assessments of pain behavior, axon reflex measurements, and immunohistochemical analyses of cutaneous innervation in an experimental animal model of diabetes. The experiments were combined with blocking the TRPA1 channel with selective antagonists Chembridge-5861528 or A-967079.ResultsIn vitro studies indicate that under physiological concentration of Ca2+, methylglyoxal and 4-hydroxynonenal produce sustained activation of the TRPA1 channel and sustained inflow of calcium. In vivo studies indicate that diabetic pain hypersensitivity is maintained by the TRPA1 channel as indicated by the antihypersensitivity effect induced by acute blocking of the TRPA1 channel. Moreover, TRPA1 channel is involved in the development of diabetic hypersensitivity as indicated by prevention of the development of pain hypersensitivity in diabetic animals treated daily with Chembridge-5861528. The diabetes-induced loss of substance P-like cutaneous innervation and that of the TRPA1 channel-mediated cutaneous axon reflex function during the later phase of diabetes were also prevented or delayed by prolonged blocking of the TRPA1 channel. No motor impairment or other obvious side-effects were observed following block of the TRPA1 channel.Conclusions Together the in vitro and in vivo results indicate that reactive compounds generated in diabetes exert, through action on the TRPA1 channel, an important role in the pathophysiology of PDN. Sustained activation of the TRPA1 channel is a plausible mechanism that contributes to the early diabetic pain hypersensitivity and the later loss of cutaneous pain fiber endings and their dysfunction with prolonged diabetes.ImplicationsBlocking the TRPA1 channel with a selective antagonist provides a promising disease-modifying treatment for PDN, with only minor, if any, side-effects.

scholarly journals TRPV1 and TRPA1 Channels Are Both Involved Downstream of Histamine-Induced Itch

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1166
Author(s):  
Jenny Wilzopolski ◽  
Manfred Kietzmann ◽  
Santosh K. Mishra ◽  
Holger Stark ◽  
Wolfgang Bäumer ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Signal Transmission ◽  
Receptor Potential ◽  
Histamine Receptor ◽  
Receptor Subtypes ◽  
Downstream Signaling ◽  
Transient Receptor ◽  
Induced Signal

Two histamine receptor subtypes (HR), namely H1R and H4R, are involved in the transmission of histamine-induced itch as key components. Although exact downstream signaling mechanisms are still elusive, transient receptor potential (TRP) ion channels play important roles in the sensation of histaminergic and non-histaminergic itch. The aim of this study was to investigate the involvement of TRPV1 and TRPA1 channels in the transmission of histaminergic itch. The potential of TRPV1 and TRPA1 inhibitors to modulate H1R- and H4R-induced signal transmission was tested in a scratching assay in mice in vivo as well as via Ca2+ imaging of murine sensory dorsal root ganglia (DRG) neurons in vitro. TRPV1 inhibition led to a reduction of H1R- and H4R- induced itch, whereas TRPA1 inhibition reduced H4R- but not H1R-induced itch. TRPV1 and TRPA1 inhibition resulted in a reduced Ca2+ influx into sensory neurons in vitro. In conclusion, these results indicate that both channels, TRPV1 and TRPA1, are involved in the transmission of histamine-induced pruritus.

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