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Journal ArticleDOI

Targeting calcium signaling in cancer therapy.

TL;DR: This review summarizes some importantCa2+ channels, transporters and Ca2+-ATPases, which have been reported to be altered in human cancer patients, and discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca2+.
About: This article is published in Acta Pharmaceutica Sinica B.The article was published on 2017-01-01 and is currently open access. It has received 389 citations till now. The article focuses on the topics: Calcium signaling & Ca2+/calmodulin-dependent protein kinase.
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Journal ArticleDOI
TL;DR: This review summarizes the recent advances of NIR-II photothermal combinational theranostics pertinent to chemotherapy, immunotherapy, radiotherapy, and photodynamic, sonodynamic, chemodynamic, gene, gas, ionic, vascular and magnetothermal therapy.
Abstract: Second near-infrared photothermal therapy (NIR-II PTT, 1000-1500 nm) has recently emerged as a new phototherapeutic modality with the advantages of deeper penetration, less energy dissipation and minimal normal-tissue toxicity over traditional first NIR PTT (750-1000 nm). However, suboptimal photothermal conversion and limited therapeutic efficacy remain the major challenges for NIR-II PTT. With the convergence in materials science, nanomedicine and biology, multifunctional NIR-II photothermal inorganic or organic materials have been extensively developed to combine NIR-II PTT with other therapeutic modalities for improved efficacies in treating life-threatening diseases including cancer and infection. This review summarizes the recent advances of NIR-II photothermal combinational theranostics pertinent to chemotherapy, immunotherapy, radiotherapy, and photodynamic, sonodynamic, chemodynamic, gene, gas, ionic, vascular and magnetothermal therapy. Potential obstacles and perspectives for future research and clinical translation of this new theranostic modality are also discussed.

378 citations

Journal ArticleDOI
TL;DR: This work presents pathfindR, another approach exploiting protein-protein interaction information and the first R package for active-subnetwork-oriented pathway enrichment analyses for class comparison omics experiments and demonstrates that literature-supported disease-related pathways ranked higher in this approach compared to the others.
Abstract: Pathway analysis is often the first choice for studying the mechanisms underlying a phenotype. However, conventional methods for pathway analysis do not take into account complex protein-protein interaction information, resulting in incomplete conclusions. Previously, numerous approaches that utilize protein-protein interaction information to enhance pathway analysis yielded superior results compared to conventional methods. Hereby, we present pathfindR, another approach exploiting protein-protein interaction information and the first R package for active-subnetwork-oriented pathway enrichment analysis for class comparison omics experiments. Using the list of genes obtained from an omics experiment comparing two groups of samples, pathfindR identifies active subnetworks in a protein-protein interaction network. It then performs pathway enrichment analyses on these identified subnetworks. To further reduce the complexity, it provides functionality for clustering the resulting pathways. Moreover, through a scoring function, the overall activity of each pathway in each sample can be estimated. We illustrate the capabilities of our pathway analysis method on three gene expression datasets and compare our results with those obtained from three popular pathway analysis tools. The results demonstrate that literature-supported disease-related pathways ranked higher in our approach compared to the others. Moreover, pathfindR identified additional pathways relevant to the conditions that were not identified by other tools, including pathways named after the conditions.

166 citations

Journal ArticleDOI
TL;DR: The role of SERCA misregulation in the control of apoptosis in various cell types and disease setting with prospective therapeutic implications is the focus ofThis review supports a model in which Ca2+ homeostasis and SERCA activity represent a nodal point that controls cell survival.

143 citations

Journal ArticleDOI
TL;DR: The involvement of IP3Rs in the regulation of both autophagy and apoptosis, therefore, directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.
Abstract: Calcium ions (Ca2+) play a complex role in orchestrating diverse cellular processes including cell death and survival. To trigger signaling cascades, intracellular Ca2+ is shuffled between the cytoplasm and the major Ca2+ stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca2+ signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca2+-release channels in the ER. IP3Rs can transfer Ca2+ to the mitochondria, thereby stimulating core metabolic pathways, but also increasing apoptosis sensitivity and inhibiting basal autophagy. On the other hand, IP3-induced Ca2+ release enhances autophagy flux by providing cytosolic Ca2+ required to execute autophagy upon various cellular stresses, including nutrient starvation, chemical mTOR inhibition or drug treatment. Similarly, IP3Rs are able to amplify Ca2+ signals from the lysosomes and therefore impact autophagic flux in response to lysosomal channels activation. Furthermore, indirect modulation of Ca2+ release through IP3Rs may also be achieved by controlling the SERCA Ca2+ pumps of the ER. Considering the complex role of autophagy in cancer development and progression as well as in response to anticancer therapies, it becomes clear that it is important to fully understand the role of the IP3R and its cellular context in this disease. In cancer cells addicted to ER-mitochondria Ca2+ fueling, IP3R inhibition lead to cancer cell death via mechanisms involving enhanced autophagy or mitotic catastrophe. Moreover, IP3Rs are the targets of several oncogenes and tumor suppressors and the functional loss of these genes, as occurring in many cancer types, can result in modified Ca2+ transport to the mitochondria and in modulation of the level of autophagic flux. Similarly, IP3R-mediated upregulation of autophagy can protect some cancer cells against NK cells-induced killing. The involvement of IP3Rs in the regulation of both autophagy and apoptosis therefore directly impact cancer cell biology and contribute to the molecular basis of tumor pathology.

117 citations


Cites background from "Targeting calcium signaling in canc..."

  • ...iP3Rs in Cancer IP3Rs control different hallmarks of cancer (97, 98)....

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Journal ArticleDOI
TL;DR: It is demonstrated that dietary cholesterol induces NASH by deregulating genes involved in metabolism, inflammation and calcium signaling to induce NASH-HCC in diethylnitrosamine-treated mice.
Abstract: The underlining mechanisms of dietary cholesterol and nonalcoholic steatohepatitis (NASH) in contributing to hepatocellular carcinoma (HCC) remain undefined. Here we demonstrated that high-fat-non-cholesterol-fed mice developed simple steatosis, whilst high-fat-high-cholesterol-fed mice developed NASH. Moreover, dietary cholesterol induced larger and more numerous NASH-HCCs than non-cholesterol-induced steatosis-HCCs in diethylnitrosamine-treated mice. NASH-HCCs displayed significantly more aberrant gene expression-enriched signaling pathways and more non-synonymous somatic mutations than steatosis-HCCs (335 ± 84/sample vs 43 ± 13/sample). Integrated genetic and expressional alterations in NASH-HCCs affected distinct genes pertinent to five pathways: calcium, insulin, cell adhesion, axon guidance and metabolism. Some of the novel aberrant gene expression, mutations and core oncogenic pathways identified in cholesterol-associated NASH-HCCs in mice were confirmed in human NASH-HCCs, which included metabolism-related genes (ALDH18A1, CAD, CHKA, POLD4, PSPH and SQLE) and recurrently mutated genes (RYR1, MTOR, SDK1, CACNA1H and RYR2). These findings add insights into the link of cholesterol to NASH and NASH-HCC and provide potential therapeutic targets.

115 citations

References
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Journal ArticleDOI
TL;DR: The universality of calcium as an intracellular messenger depends on its enormous versatility, which is exploited to control processes as diverse as fertilization, proliferation, development, learning and memory, contraction and secretion.
Abstract: The universality of calcium as an intracellular messenger depends on its enormous versatility. Cells have a calcium signalling toolkit with many components that can be mixed and matched to create a wide range of spatial and temporal signals. This versatility is exploited to control processes as diverse as fertilization, proliferation, development, learning and memory, contraction and secretion, and must be accomplished within the context of calcium being highly toxic. Exceeding its normal spatial and temporal boundaries can result in cell death through both necrosis and apoptosis.

5,369 citations


"Targeting calcium signaling in canc..." refers background in this paper

  • ...com/locate/apsb Acta Pharmaceutica Sinica B Acta Pharmaceutica Sinica B 2017;7(1):3–17...

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  • ...The intracellular Ca2þ homeostasis is governed by a network composed of various Ca2þ channels and transporters: (1) IP3R or ryanodine receptor (RyR) mediating Ca2þ release from endoplasmic/ sarcoplasmic reticulum (ER/SR); (2) Ca2þ-ATPase pumping Ca2þ from cytosol back to ER/SR or extracellular space; (3) Ca2þ channels or transporters allowing Ca2þ influx across plasma membrane (PM) from extracellular Ca2þ reservoir, such as voltage-gated Ca2þ channel (VGCC), transient receptor potential channel (TRP), Ca2þ releaseactivated Ca2þ channel (CRAC), Naþ/Ca2þ exchanger (NCX) and purinergic receptor; (4) mitochondrial Ca2þ uniporter (MCU) regulating mitochondrial Ca2þ uptakes (Fig....

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  • ...proteins: (1) IP3Rs mediating Ca 2þ release from endoplasmic reticulum (ER); (2) Ca2þ-ATPases pumping Ca2þ from cytosol to the ER or to extracellular space; (3) plasma membrane Ca2þ channels or...

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  • ...copyranosyl-20(S)-protopanaxadiol; CaM, calmodulin; CaMKII, calmodulin-dependent protein kinase II; CBD, sazepine; CRAC, Ca2þ release-activated Ca2þ channel; CTL, cytotoxic T cells; CYP3A4, cytochrome P450 3A4; m; HCX, Hþ/Ca2þ exchangers; IP3, inositol 1,4,5-trisphosphate; IP3R (1, 2, 3), IP3 receptor (type 1, type 2, type ochondrial Ca2þ uniporter; MCUR1, MCU uniporter regulator 1; MICU (1, 2, 3), mitochondrial calcium uptake ght-chain kinase; NCX, Naþ/Ca2þ exchanger; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factorOSCC, oral squamous cell carcinoma cells; PKC, protein kinase C; PM, plasma membrane; PMCA, plasma y transition pore; ROS, reactive oxygen species; RyR, ryanodine receptor; SERCA, SR/ER Ca2þ-ATPase; SOCE, y pathway Ca2þ-ATPase; TEA, tetraethylammonium; TG, thapsigargin; TPC2, two-pore channel 2; TRIM, 1-(2P (A, C, M, ML, N, P, V), transient receptor potential (ankyrin, canonical, melastatin, mucolipin, no anilloid); VGCC, voltage-gated Ca2þ channel ursing and Health Innovation, The University of Texas at Arlington, LS Building 239, 501 S....

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Journal ArticleDOI
TL;DR: The distinct structures and patterns of regulation of these three families of Ca(2+) channels provide a flexible array of Ca('s 2+) entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca (2+) entry by second messenger pathways and interacting proteins.
Abstract: Voltage-gated Ca(2+) channels mediate Ca(2+) entry into cells in response to membrane depolarization. Electrophysiological studies reveal different Ca(2+) currents designated L-, N-, P-, Q-, R-, and T-type. The high-voltage-activated Ca(2+) channels that have been characterized biochemically are complexes of a pore-forming alpha1 subunit of approximately 190-250 kDa; a transmembrane, disulfide-linked complex of alpha2 and delta subunits; an intracellular beta subunit; and in some cases a transmembrane gamma subunit. Ten alpha1 subunits, four alpha2delta complexes, four beta subunits, and two gamma subunits are known. The Cav1 family of alpha1 subunits conduct L-type Ca(2+) currents, which initiate muscle contraction, endocrine secretion, and gene transcription, and are regulated primarily by second messenger-activated protein phosphorylation pathways. The Cav2 family of alpha1 subunits conduct N-type, P/Q-type, and R-type Ca(2+) currents, which initiate rapid synaptic transmission and are regulated primarily by direct interaction with G proteins and SNARE proteins and secondarily by protein phosphorylation. The Cav3 family of alpha1 subunits conduct T-type Ca(2+) currents, which are activated and inactivated more rapidly and at more negative membrane potentials than other Ca(2+) current types. The distinct structures and patterns of regulation of these three families of Ca(2+) channels provide a flexible array of Ca(2+) entry pathways in response to changes in membrane potential and a range of possibilities for regulation of Ca(2+) entry by second messenger pathways and interacting proteins.

2,330 citations

Journal ArticleDOI
TL;DR: A "two-hit" hypothesis is developed, in which Ca(2+) plus another pathological stimulus can bring about mitochondrial dysfunction, and the delicate balance between the positive and negative effects of Ca( 2+) and the signaling events that perturb this balance is highlighted.
Abstract: The mitochondrion is at the core of cellular energy metabolism, being the site of most ATP generation. Calcium is a key regulator of mitochondrial function and acts at several levels within the organelle to stimulate ATP synthesis. However, the dysregulation of mitochondrial Ca(2+) homeostasis is now recognized to play a key role in several pathologies. For example, mitochondrial matrix Ca(2+) overload can lead to enhanced generation of reactive oxygen species, triggering of the permeability transition pore, and cytochrome c release, leading to apoptosis. Despite progress regarding the independent roles of both Ca(2+) and mitochondrial dysfunction in disease, the molecular mechanisms by which Ca(2+) can elicit mitochondrial dysfunction remain elusive. This review highlights the delicate balance between the positive and negative effects of Ca(2+) and the signaling events that perturb this balance. Overall, a "two-hit" hypothesis is developed, in which Ca(2+) plus another pathological stimulus can bring about mitochondrial dysfunction.

2,265 citations

Journal ArticleDOI
30 Apr 1998-Nature
TL;DR: It is reported that oscillations reduce the effective Ca2+ threshold for activating transcription factors, thereby increasing signal detection at low levels of stimulation and providing direct evidence that [Ca2+]i oscillations increase both the efficacy and the information content of Ca2+, leading to gene expression and cell differentiation.
Abstract: Cytosolic calcium ([Ca2+]i) oscillations are a nearly universal mode of signalling in excitable and non-excitable cells. Although Ca2+ is known to mediate a diverse array of cell functions, it is not known whether oscillations contribute to the efficiency or specificity of signalling or are merely an inevitable consequence of the feedback control of [Ca2+]i. We have developed a Ca2+ clamp technique to investigate the roles of oscillation amplitude and frequency in regulating gene expression driven by the proinflammatory transcription factors NF-AT, Oct/OAP and NF-kappaB. Here we report that oscillations reduce the effective Ca2+ threshold for activating transcription factors, thereby increasing signal detection at low levels of stimulation. In addition, specificity is encoded by the oscillation frequency: rapid oscillations stimulate all three transcription factors, whereas infrequent oscillations activate only NF-kappaB. The genes encoding the cytokines interleukin (IL)-2 and IL-8 are also frequency-sensitive in a way that reflects their degree of dependence on NF-AT versus NF-kappaB. Our results provide direct evidence that [Ca2+]i oscillations increase both the efficacy and the information content of Ca2+ signals that lead to gene expression and cell differentiation.

1,903 citations

Journal ArticleDOI
TL;DR: Although the specificity of 2APB with respect to the intracellular signaling system was not fully established, it is the first candidate for a membrane-penetrable modulator of Ins(1,4,5)P3 receptor, and it should be a useful tool to investigate the physiological role of the Ins(2,3,3)P2 receptor in various cells.
Abstract: The effects of a novel membrane-penetrable modulator, 2APB (2-aminoethoxy diphenyl borate), on Ins(1,4,5)P3-induced Ca2+ release were examined. 2APB inhibited Ins(1,4,5)P3-induced Ca2+ release from rat cerebellar microsomal preparations without affecting [3H]Ins(1,4,5)P3 binding to its receptor. The IC50 value (concentration producing 50% inhibition) of 2APB for inhibition of Ins(1,4,5)P3 (100 nM) induced Ca2+ release was 42 microM. Further increase in the concentration of 2APB (more than 90 microM) caused a gradual release of Ca2+ from cerebellar microsomal preparations. Addition of 2APB to the extracellular environment inhibited the cytosolic Ca2+ ([Ca2+]c) rise in intact cells such as human platelets and neutrophils stimulated by thromboxane-mimetic STA2 or thrombin, and leukotriene B4 (LTB4) or formyl-methionine-leucine-phenylalanine (FMLP), respectively. 2APB inhibited the contraction of thoracic aorta isolated from rabbits induced by angiotensin II (AII), STA2, and norepinephrine in a non-competitive manner, but showed no effect on the contraction of potassium-depolarized muscle. 2APB had no effect on the Ca2+ release from the ryanodine-sensitive Ca2+ store prepared from rat leg skeletal muscle and heart. Although the specificity of 2APB with respect to the intracellular signaling system was not fully established, 2APB is the first candidate for a membrane-penetrable modulator of Ins(1,4,5)P3 receptor, and it should be a useful tool to investigate the physiological role of the Ins(1,4,5)P3 receptor in various cells.

893 citations