The large Trp gene family encodes transient receptor potential (TRP) proteins that form novel cation-selective ion channels. In mammals, 28 Trp channel genes have been identified. TRP proteins exhibit diverse permeation and gating properties and are involved in a plethora of physiologic functions with a strong impact on cellular sensing and signaling pathways. Indeed, mutations in human genes encoding TRP channels, the so-called "TRP channelopathies," are responsible for a number of hereditary diseases that affect the musculoskeletal, cardiovascular, genitourinary, and nervous systems. This review gives an overview of the functional properties of mammalian TRP channels, describes their roles in acquired and hereditary diseases, and discusses their potential as drug targets for therapeutic intervention.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

The calcium signal is a powerful and multifaceted tool by which cells can achieve specific outcomes. Cellular machinery important in tumour progression is often driven or influenced by changes in calcium ions; in some cases this regulation occurs within spatially defined regions. Over the past decade there has been a deeper understanding of how calcium signalling is remodelled in some cancers and the consequences of calcium signalling on key events such as proliferation, invasion and sensitivity to cell death. Specific calcium signalling pathways have also now been identified as playing important roles in the establishment and maintenance of multidrug resistance and the tumour microenvironment.

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The calcium-cancer signalling nexus

The multi-factorial nature of clinical multidrug resistance in cancer.

Extracellular Vesicles (EVs) have received considerable attention in recent years, both as mediators of intercellular communication pathways that lead to tumor progression, and as potential sources for discovery of novel cancer biomarkers. For many years, research on EVs has mainly investigated either the mechanism of biogenesis and cargo selection and incorporation, or the methods of EV isolation from available body fluids for biomarker discovery. Recent studies have highlighted the existence of different populations of cancer-derived EVs, with distinct molecular cargo, thus pointing to the possibility that the various EV populations might play diverse roles in cancer and that this does not happen randomly. However, data attributing cancer specific intercellular functions to given populations of EVs are still limited. A deeper functional, biochemical and molecular characterization of the various EV classes might identify more selective clinical markers, and significantly advance our knowledge of the pathogenesis and disease progression of many cancer types.

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Focus on Extracellular Vesicles: New Frontiers of Cell-to-Cell Communication in Cancer

Colorectal cancer (CRC) is a public health problem. It is the third most common cancer in the world, with nearly 1.8 million new cases diagnosed in 2018. The only curative treatment is surgery, especially for early tumor stages. When there is locoregional or distant invasion, chemotherapy can be introduced, in particular 5-fluorouracil (5-FU). However, the disease can become tolerant to these pharmaceutical treatments: resistance emerges, leading to early tumor recurrence. Different mechanisms can explain this 5-FU resistance. Some are disease-specific, whereas others, such as drug efflux, are evolutionarily conserved. These mechanisms are numerous and complex and can occur simultaneously in cells exposed to 5-FU. In this review, we construct a global outline of different mechanisms from disruption of 5-FU-metabolic enzymes and classic cellular processes (apoptosis, autophagy, glucose metabolism, oxidative stress, respiration, and cell cycle perturbation) to drug transporters and epithelial-mesenchymal transition induction. Particular interest is directed to tumor microenvironment function as well as epigenetic alterations and miRNA dysregulation, which are the more promising processes that will be the subject of much research in the future.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cas.14532

5-Fluorouracil resistance mechanisms in colorectal cancer: From classical pathways to promising processes

An attractive strategy to overcome multidrug resistance in cancer chemotherapy is to suppress P-glycoprotein (P-gp), which is a pump overproduced in cancer cells to remove cytotoxic drugs from cells. In the present study, a Ca2+-permeable channel TRPC5 was found to be overproduced together with P-gp in adriamycin-resistant breast cancer cell line MCF-7/ADM. Suppressing TRPC5 activity/expression reduced the P-gp induction and caused a remarkable reversal of adriamycin resistance in MCF-7/ADM. In an athymic nude mouse model of adriamycin-resistant human breast tumor, suppressing TRPC5 decreased the growth of tumor xenografts. Nuclear factor of activated T cells isoform c3 (NFATc3) was the transcriptional factor that links the TRPC5 activity to P-gp production. Together, we demonstrated an essential role of TRPC5–NFATc3–P-gp signaling cascade in P-gp induction in drug-resistant cancer cells.

https://www.pnas.org/content/pnas/109/40/16282.full.pdf

Transient receptor potential channel TRPC5 is essential for P-glycoprotein induction in drug-resistant cancer cells

Blood pressure is maintained within a normal physiological range by a sophisticated regulatory mechanism. Baroreceptors serve as a frontline sensor to detect the change in blood pressure. Nerve signals are then sent to the cardiovascular control centre in the brain in order to stimulate baroreflex responses. Here, we identify TRPC5 channels as a mechanical sensor in aortic baroreceptors. In Trpc5 knockout mice, the pressure-induced action potential firings in the afferent nerve and the baroreflex-mediated heart rate reduction are attenuated. Telemetric measurements of blood pressure demonstrate that Trpc5 knockout mice display severe daily blood pressure fluctuation. Our results suggest that TRPC5 channels represent a key pressure transducer in the baroreceptors and play an important role in maintaining blood pressure stability. Because baroreceptor dysfunction contributes to a variety of cardiovascular diseases including hypertension, heart failure and myocardial infarction, our findings may have important future clinical implications.

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TRPC5 channels participate in pressure-sensing in aortic baroreceptors.

Atherosclerosis is a chronic inflammatory arterial disease characterized by build-up of atheromatous plaque, which narrows the lumen of arteries. Hypercholesterolemia and excessive oxidative stress in arterial walls are among the main causative factors of atherosclerosis. Transient receptor potential channel M2 (TRPM2) is a Ca2+-permeable cation channel activated by oxidative stress. However, the role of TRPM2 in atherosclerosis in animal models is not well studied. In the present study, with the use of adeno-associated virus (AAV)-PCSK9 and TRPM2 knockout (TRPM2−/−) mice, we determined the role of TRPM2 in hypercholesterolemia-induced atherosclerosis. Our results demonstrated that TRPM2 knockout reduced atherosclerotic plaque area in analysis of En face Oil Red O staining of both whole aortas and aortic-root thin sections. Furthermore, TRPM2 knockout reduced the expression of CD68, α-SMA, and PCNA in the plaque region, suggesting a role of TRPM2 in promoting macrophage infiltration and smooth-muscle cell migration into the lesion area. Moreover, TRPM2 knockout reduced the expression of ICAM-1, MCP-1, and TNFα and decreased the ROS level in the plaque region, suggesting a role of TRPM2 in enhancing monocyte adhesion and promoting vascular inflammation. In bone-marrow-derived macrophages and primary cultured arterial endothelial cells, TRPM2 knockout reduced the production of inflammatory cytokines/factors and decreased ROS production. In addition, a TRPM2 antagonist N-(p-amylcinnamoyl) anthranilic acid (ACA) was able to inhibit atherosclerotic development in an ApoE−/− mouse model of atherosclerosis. Taken together, the findings of our study demonstrated that TRPM2 contributes to the progression of hypercholesterolemia-induced atherosclerosis. Mechanistically, TRPM2 channels may provide an essential link that can connect ROS to Ca2+ and inflammation, consequently promoting atherosclerotic progression.

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TRPM2 Promotes Atherosclerotic Progression in a Mouse Model of Atherosclerosis

Nature Communications 7: Article number: 11947 (2016); Published online: 14 July 2016; Updated: 23 March 2018 It has come to our attention that errors were made in measurements of resting blood pressure reported in this article, in Fig. 8 and in the ‘Results’ section entitled ‘Deficiency of baroreceptor function in Trpc5 knockout (Trpc5−/−) mice’.

/pdf/author-correction-trpc5-channels-participate-in-pressure-4zwevqpied.pdf

Chun Yin Lo

Papers

Transient receptor potential channel TRPC5 is essential for P-glycoprotein induction in drug-resistant cancer cells

TRPC5 channels participate in pressure-sensing in aortic baroreceptors.

TRPM2 Promotes Atherosclerotic Progression in a Mouse Model of Atherosclerosis

Author Correction: TRPC5 channels participate in pressure-sensing in aortic baroreceptors