The regulatory and modulatory roles of TRP family channels in malignant tumors and relevant therapeutic strategies

Abstract

Transient receptor potential (TRP) channels are one primary type of calcium (Ca²⁺) permeable channels, and those relevant transmembrane and intracellular TRP channels were previously thought to be mainly associated with the regulation of cardiovascular and neuronal systems. Nowadays, however, accumulating evidence shows that those TRP channels are also responsible for tumorigenesis and progression, inducing tumor invasion and metastasis. However, the overall underlying mechanisms and possible signaling transduction pathways that TRP channels in malignant tumors might still remain elusive. Therefore, in this review, we focus on the linkage between TRP channels and the significant characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, immune surveillance evasion, and the alterations of relevant tumor micro-environment. Moreover, we also have discussed the expression of relevant TRP channels in various forms of cancer and the relevant inhibitors' efficacy. The chemo-sensitivity of the anti-cancer drugs of various acting mechanisms and the potential clinical applications are also presented. Furthermore, it would be enlightening to provide possible novel therapeutic approaches to counteract malignant tumors regarding the intervention of calcium channels of this type.

Keywords: 4α-PDD, 4α-phorbol-12,13-didecanoate; ABCB, ATP-binding cassette B1; AKT, protein kinase B; ALA, alpha lipoic acid; AMPK, AMP-activated protein kinase; APB, aminoethoxydiphenyl borate; ATP, adenosine triphosphate; CBD, cannabidiol; CRAC, Ca2+ release-activated Ca2+ channel; CaR, calcium-sensing receptor; CaSR, calcium sensing receptor; Cancer progression; DAG, diacylglycerol; DBTRG, Denver Brain Tumor Research Group; ECFC, endothelial colony-forming cells; ECM, enhanced extracellular matrix; EGF, epidermal growth factor; EMT, epithelial–mesenchymal transition; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ETS, erythroblastosis virus E26 oncogene homolog; FAK, focal adhesion kinase; GADD, growth arrest and DNA damage-inducible gene; GC, gastric cancer; GPCR, G-protein coupled receptor; GSC, glioma stem-like cells; GSK, glycogen synthase kinase; HCC, hepatocellular carcinoma; HIF, hypoxia-induced factor; HSC, hematopoietic stem cells; IP3R, inositol triphosphate receptor; Intracellular mechanism; KO, knockout; LOX, lipoxygenase; LPS, lipopolysaccharide; LRP, lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase; MLKL, mixed lineage kinase domain-like protein; MMP, matrix metalloproteinases; NEDD4, neural precursor cell expressed, developmentally down-regulated 4; NFAT, nuclear factor of activated T-cells; NLRP3, NLR family pyrin domain containing 3; NO, nitro oxide; NSCLC, non-small cell lung cancer; Nrf2, nuclear factor erythroid 2-related factor 2; P-gp, P-glycoprotein; PCa, prostate cancer; PDAC, pancreatic ductal adenocarcinoma; PHD, prolyl hydroxylases; PI3K, phosphoinositide 3-kinase; PKC, protein kinase C; PKD, polycystic kidney disease; PLC, phospholipase C; Programmed cancer cell death; RNS/ROS, reactive nitrogen species/reactive oxygen species; RTX, resiniferatoxin; SMAD, Caenorhabditis elegans protein (Sma) and mothers against decapentaplegic (Mad); SOCE, store operated calcium entry; SOR, soricimed; STIM1, stromal interaction molecules 1; TEC, tumor endothelial cells; TGF, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TRP channels; TRPA/C/M/ML/N/P/V, transient receptor potential ankyrin/canonical/melastatin/mucolipon/NOMPC/polycystin/vanilloid; Targeted tumor therapy; Tumor microenvironment; Tumor-associated immunocytes; UPR, unfolded protein response; VEGF, vascular endothelial growth factor; VIP, vasoactive intestinal peptide; VPAC, vasoactive intestinal peptide receptor subtype; mTOR, mammalian target of rapamycin; pFRG/RTN, parafacial respiratory group/retrotrapezoid nucleus.