WAS

Gene Summary

Gene:WAS; Wiskott-Aldrich syndrome
Aliases: THC, IMD2, SCNX, THC1, WASP, WASPA
Location:Xp11.23
Summary: The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. Wiskott-Aldrich syndrome is a rare, inherited, X-linked, recessive disease characterized by immune dysregulation and microthrombocytopenia, and is caused by mutations in the WAS gene. The WAS gene product is a cytoplasmic protein, expressed exclusively in hematopoietic cells, which show signalling and cytoskeletal abnormalities in WAS patients. A transcript variant arising as a result of alternative promoter usage, and containing a different 5' UTR sequence, has been described, however, its full-length nature is not known. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:wiskott-Aldrich syndrome protein
Source:NCBIAccessed: 13 March, 2017

Ontology:

What does this gene/protein do?
Show (18)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 13 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • X Chromosome
Tag cloud generated 13 March, 2017 using data from PubMed, MeSH and CancerIndex

Latest Publications: WAS (cancer-related)

Zhou T, Wang CH, Yan H, et al.
Inhibition of the Rac1-WAVE2-Arp2/3 signaling pathway promotes radiosensitivity via downregulation of cofilin-1 in U251 human glioma cells.
Mol Med Rep. 2016; 13(5):4414-20 [PubMed] Related Publications
The Ras-related C3 botulinum toxin substrate 1 (Rac1)-WASP-family verprolin-homologous protein-2 (WAVE2)-actin-related protein 2/3 (Arp2/3) signaling pathway has been identified to be involved in cell migration and invasion in various types of cancer cell. Cofilin‑1 (CFL‑1), which is regulated by the Rac1‑WAVE2‑Arp2/3 signaling pathway, may promote radioresistance in glioma. Therefore, the present study aimed to investigate the potential role of the Rac1‑WAVE2‑Arp2/3 signaling pathway in radioresistance in U251 human glioma cells and elucidate its affect on CFL‑1 expression. Western blot analysis was performed to evaluate the protein expression of CFL‑1. In the present study, Rac1 was inhibited by NSC 23766, WAVE2 was inhibited by transfection with short hairpin (sh)RNA‑WAVE2 using Lipofectamine™ 2000 and Arp2/3 was inhibited by CK‑666. Cell viability was measured using the 3‑(4,5‑dimethylthiazol‑2‑yl)-2,5‑diphenyltetrazolium bromide assay, the cell migration ability was examined by a wound‑healing assay, and the cell invasion ability was assessed using a Transwell culture chamber system. The results showed that inhibition of the Rac1‑WAVE2‑Arp2/3 signaling pathway using NSC 23766, shRNA‑WAVE2 or CK‑666 reduced the cell viability, migration and invasion abilities in U251 human glioma cells, concordant with a reduced expression of CFL‑1. Furthermore, the expression of CFL‑1 was significantly increased in radioresistant U251 glioma cells when compared with normal U251 human glioma cells. These findings indicate that inhibition of the Rac1‑WAVE2‑Arp2/3 signaling pathway may promote radiosensitivity, which may partially result from the downregulation of CFL‑1 in U251 human glioma cells.

Zhang Z, Wu B, Chai W, et al.
Knockdown of WAVE1 enhances apoptosis of leukemia cells by downregulating autophagy.
Int J Oncol. 2016; 48(6):2647-56 [PubMed] Related Publications
Chemoresistance of leukemia constitutes a great challenge for successful treatment of leukemia. Autophagy has recently attracted increasing attention for its role in conferring resistance to various conventional anti-neoplastic regiments. In the present study, the authors showed that WAVE1, a member of WASP family verprolin-homologous proteins, is a critical regulator of chemoresistance during autophagy. It is positively correlated with clinical status in pediatric acute myeloblastic leukemia (AML) and leukemia cell lines. The knockdown of WAVE1 expression decreased autophagy was accompanied by an upregulation of autophagic marker microtubule-associated protein light chain 3 (LC3)-Ⅱ, a degradation of SQSTM1/sequestosome 1 (p62) and the formation of autophagosomes. Moreover, a suppression of WAVE1 expression increased the sensitivity of leukemia cells to chemotherapy and apoptosis, and depletion of WAVE1 expression promoted the translocation of Bcl-2 from mitochondria into the cytoplasm. In addition, a knockdown of PI3K-Ⅲ expression significantly inhibited WAVE1-mediated autophagy. Furthermore, suppression of WAVE1 expression blocked the interactions between Beclin1 and PI3K-Ⅲ and the disassociation of Beclin1-Bcl-2 during enhanced autophagy. The above results suggested that WAVE1 is a critical pro-autophagic protein capable of enhancing cell survival and regulating chemoresistance in leukemia cells potentially through the Beclin1/Bcl-2 and Beclin1/PI3K-Ⅲ complex-dependent pathways.

García E, Ragazzini C, Yu X, et al.
WIP and WICH/WIRE co-ordinately control invadopodium formation and maturation in human breast cancer cell invasion.
Sci Rep. 2016; 6:23590 [PubMed] Free Access to Full Article Related Publications
Cancer cells form actin-rich degradative protrusions (invasive pseudopods and invadopodia), which allows their efficient dispersal during metastasis. Using biochemical and advanced imaging approaches, we demonstrate that the N-WASP-interactors WIP and WICH/WIRE play non-redundant roles in cancer cell invasion. WIP interacts with N-WASP and cortactin and is essential for invadopodium assembly, whereas WICH/WIRE regulates N-WASP activation to control invadopodium maturation and degradative activity. Our data also show that Nck interaction with WIP and WICH/WIRE modulates invadopodium maturation; changes in WIP and WICH/WIRE levels induce differential distribution of Nck. We show that WIP can replace WICH/WIRE functions and that elevated WIP levels correlate with high invasiveness. These findings identify a role for WICH/WIRE in invasiveness and highlight WIP as a hub for signaling molecule recruitment during invadopodium generation and cancer progression, as well as a potential diagnostic biomarker and an optimal target for therapeutic approaches.

Weeks HP, Sanders AJ, Kynaston HG, Jiang WG
The Association Between WAVE1 and -3 and the ARP2/3 Complex in PC 3 Cells.
Anticancer Res. 2016; 36(3):1135-42 [PubMed] Related Publications
BACKGROUND: Actin polymerisation is stimulated by the actin-related protein (ARP) 2/3 complex and drives cell migration. This complex is activated by Wiskott-Aldrich syndrome protein family (WASP) verprolin homologous protein (WAVE) proteins. WAVE1 and -3 have been implicated in the aggressiveness of metastatic prostate cancer cells.
MATERIALS AND METHODS: Cell growth, motility and invasion were analyzed in WAVE1- and WAVE3-knockdown PC-3 cells along with the ARP2/3 inhibitor, CK-0944636. Confocal microscopy was adopted to examine protein co-localisation. Immunoprecipitation approaches were used to determine protein tyrosine phosphorylation.
RESULTS: Cell growth suppression was observed with WAVE3 knockdown and ARP2/3 inhibition. Reduced cell invasion effects observed with WAVE1 knockdown appeared to be rescued by ARP2/3 inhibition. WAVE1 and WAVE3 and ARP2 co-localisation was lost in PC-3 WAVE-knockdown cells, while increased ARP2 tyrosine phosphorylation was observed with WAVE3 knockdown.
CONCLUSION: These results implicate a contributory role of WAVE1 and -3 to the metastatic phenotype of PC-3 cells through their interaction with the ARP2/3 complex.

Yoysungnoen B, Bhattarakosol P, Changtam C, Patumraj S
Effects of Tetrahydrocurcumin on Tumor Growth and Cellular Signaling in Cervical Cancer Xenografts in Nude Mice.
Biomed Res Int. 2016; 2016:1781208 [PubMed] Free Access to Full Article Related Publications
Tetrahydrocurcumin (THC) is a stable metabolite of curcumin (CUR) in physiological systems. The mechanism underlying the anticancer effect of THC is not completely understood. In the present study, we investigated the effects of THC on tumor growth and cellular signaling in cervical cancer xenografts in nude mice. Cervical cancer cells (CaSki) were subcutaneously injected in nude mice to establish tumors. One month after the injection, mice were orally administered vehicle or 100, 300, and 500 mg/kg of THC daily for 30 consecutive days. Relative tumor volume (RTV) was measured every 3-4 days. COX-2, EGFR, p-ERK1&2, p-AKT, and Ki-67 expressions were measured by immunohistochemistry whereas cell apoptosis was detected by TUNELS method. THC treatments at the doses of 100, 300, and 500 mg/kg statistically retarded the RTV by 70.40%, 76.41%, and 77.93%, respectively. The CaSki + vehicle group also showed significantly increased COX-2, EGFR, p-ERK1&2, and p-AKT; however they were attenuated by all treatments with THC. Ki-67 overexpression and a decreasing of cell apoptosis were found in CaSki + vehicle group, but these findings were reversed after the THC treatments.

Kampa-Schittenhelm KM, Salitzky O, Akmut F, et al.
Dronabinol has preferential antileukemic activity in acute lymphoblastic and myeloid leukemia with lymphoid differentiation patterns.
BMC Cancer. 2016; 16:25 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: It has been previously demonstrated in several cancer models, that Dronabinol (THC) may have anti-tumor activity--however, controversial data exists for acute leukemia. We have anecdotal evidence that THC may have contributed to disease control in a patient with acute undifferentiated leukemia.
METHODS: To test this hypothesis, we evaluated the antileukemic efficacy of THC in several leukemia cell lines and native leukemia blasts cultured ex vivo. Expression analysis for the CB1/2 receptors was performed by Western immunoblotting and flow cytometry. CB-receptor antagonists as well as a CRISPR double nickase knockdown approach were used to evaluate for receptor specificity of the observed proapoptotic effects.
RESULTS: Meaningful antiproliferative as well as proapoptotic effects were demonstrated in a subset of cases--with a preference of leukemia cells from the lymphatic lineage or acute myeloid leukemia cells expressing lymphatic markers. Induction of apoptosis was mediated via CB1 as well as CB2, and expression of CB receptors was a prerequisite for therapy response in our models. Importantly, we demonstrate that antileukemic concentrations are achievable in vivo.
CONCLUSION: Our study provides rigorous data to support clinical evaluation of THC as a low-toxic therapy option in a well defined subset of acute leukemia patients.

Lohmer LL, Clay MR, Naegeli KM, et al.
A Sensitized Screen for Genes Promoting Invadopodia Function In Vivo: CDC-42 and Rab GDI-1 Direct Distinct Aspects of Invadopodia Formation.
PLoS Genet. 2016; 12(1):e1005786 [PubMed] Free Access to Full Article Related Publications
Invadopodia are specialized membrane protrusions composed of F-actin, actin regulators, signaling proteins, and a dynamically trafficked invadopodial membrane that drive cell invasion through basement membrane (BM) barriers in development and cancer. Due to the challenges of studying invasion in vivo, mechanisms controlling invadopodia formation in their native environments remain poorly understood. We performed a sensitized genome-wide RNAi screen and identified 13 potential regulators of invadopodia during anchor cell (AC) invasion into the vulval epithelium in C. elegans. Confirming the specificity of this screen, we identified the Rho GTPase cdc-42, which mediates invadopodia formation in many cancer cell lines. Using live-cell imaging, we show that CDC-42 localizes to the AC-BM interface and is activated by an unidentified vulval signal(s) that induces invasion. CDC-42 is required for the invasive membrane localization of WSP-1 (N-WASP), a CDC-42 effector that promotes polymerization of F-actin. Loss of CDC-42 or WSP-1 resulted in fewer invadopodia and delayed BM breaching. We also characterized a novel invadopodia regulator, gdi-1 (Rab GDP dissociation inhibitor), which mediates membrane trafficking. We show that GDI-1 functions in the AC to promote invadopodia formation. In the absence of GDI-1, the specialized invadopodial membrane was no longer trafficked normally to the invasive membrane, and instead was distributed to plasma membrane throughout the cell. Surprisingly, the pro-invasive signal(s) from the vulval cells also controls GDI-1 activity and invadopodial membrane trafficking. These studies represent the first in vivo screen for genes regulating invadopodia and demonstrate that invadopodia formation requires the integration of distinct cellular processes that are coordinated by an extracellular cue.

Lin CH, Chang CY, Lee KR, et al.
Flavones inhibit breast cancer proliferation through the Akt/FOXO3a signaling pathway.
BMC Cancer. 2015; 15:958 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Flavones found in plants display various biological activities, including anti-allergic, anti-viral, anti-inflammatory, anti-oxidation, and anti-tumor effects. In this study, we investigated the anti-tumor effects of flavone, apigenin and luteolin on human breast cancer cells.
METHODS: The anti-cancer activity of flavone, apigenin and luteolin was investigated using the MTS assay. Apoptosis was analyzed by Hoechst 33342 staining, flow cytometry and western blot. Cell migration was determined using the culture inserts and xCELLigence real-time cell analyzer instrument equipped with a CIM-plate 16. Real-time quantitative PCR and western blot were used to determine the signaling pathway elicited by flavone, apigenin and luteolin.
RESULTS: Flavone, apigenin and luteolin showed potent inhibitory effects on the proliferation of Hs578T, MDA-MB-231 and MCF-7 breast cancer cells in a concentration and time-dependent manner. The ability of flavone, apigenin and luteolin to inhibit the growth of breast cancer cells through apoptosis was confirmed by Hoechst33342 staining and the induction of sub-G1 phase of the cell cycle. Flavone, apigenin and luteolin induced forkhead box O3 (FOXO3a) expression by inhibiting Phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB)/Akt. This subsequently elevated the expression of FOXO3a target genes, including the Cyclin-dependent kinase inhibitors p21Cip1 (p21) and p27kip1 (p27), which increased the levels of activated poly(ADP) polymerase (PARP) and cytochrome c.
CONCLUSION: Taken together, these data demonstrated that flavone, apigenin and luteolin induced cell cycle arrest and apoptosis in breast cancer cells through inhibiting PI3K/Akt activation and increasing FOXO3a activation, which suggest that flavone, apigenin and luteolin will be the potential leads for the preventing and treating of breast cancer.

Schwickert A, Weghake E, Brüggemann K, et al.
microRNA miR-142-3p Inhibits Breast Cancer Cell Invasiveness by Synchronous Targeting of WASL, Integrin Alpha V, and Additional Cytoskeletal Elements.
PLoS One. 2015; 10(12):e0143993 [PubMed] Free Access to Full Article Related Publications
MicroRNAs (miRNAs, micro ribonucleic acids) are pivotal post-transcriptional regulators of gene expression. These endogenous small non-coding RNAs play significant roles in tumorigenesis and tumor progression. miR-142-3p expression is dysregulated in several breast cancer subtypes. We aimed at investigating the role of miR-142-3p in breast cancer cell invasiveness. Supported by transcriptomic Affymetrix array analysis and confirmatory investigations at the mRNA and protein level, we demonstrate that overexpression of miR-142-3p in MDA-MB-231, MDA-MB-468 and MCF-7 breast cancer cells leads to downregulation of WASL (Wiskott-Aldrich syndrome-like, protein: N-WASP), Integrin-αV, RAC1, and CFL2, molecules implicated in cytoskeletal regulation and cell motility. ROCK2, IL6ST, KLF4, PGRMC2 and ADCY9 were identified as additional targets in a subset of cell lines. Decreased Matrigel invasiveness was associated with the miR-142-3p-induced expression changes. Confocal immunofluorescence microscopy, nanoscale atomic force microscopy and digital holographic microscopy revealed a change in cell morphology as well as a reduced cell volume and size. A more cortical actin distribution and a loss of membrane protrusions were observed in cells overexpressing miR-142-3p. Luciferase activation assays confirmed direct miR-142-3p-dependent regulation of the 3'-untranslated region of ITGAV and WASL. siRNA-mediated depletion of ITGAV and WASL resulted in a significant reduction of cellular invasiveness, highlighting the contribution of these factors to the miRNA-dependent invasion phenotype. While knockdown of WASL significantly reduced the number of membrane protrusions compared to controls, knockdown of ITGAV resulted in a decreased cell volume, indicating differential contributions of these factors to the miR-142-3p-induced phenotype. Our data identify WASL, ITGAV and several additional cytoskeleton-associated molecules as novel invasion-promoting targets of miR-142-3p in breast cancer.

Tseng RC, Chang JW, Mao JS, et al.
Growth-arrest-specific 7C protein inhibits tumor metastasis via the N-WASP/FAK/F-actin and hnRNP U/β-TrCP/β-catenin pathways in lung cancer.
Oncotarget. 2015; 6(42):44207-21 [PubMed] Free Access to Full Article Related Publications
Growth-arrest-specific 7 (GAS7) belongs to a group of adaptor proteins that coordinate the actin cytoskeleton. Among human GAS7 isoforms, only GAS7C possesses a Src homology 3 domain. We report here that GAS7C acts as a migration suppressor and can serve as a prognostic biomarker in lung cancer. GAS7C overexpression reduces lung cancer migration, whereas GAS7C knockdown enhances cancer cell migration. Importantly, ectopically overexpressed GAS7C binds tightly with N-WASP thus inactivates the fibronectin/integrin/FAK pathway, which in turn leads to the suppression of F-actin dynamics. In addition, overexpression of GAS7C sequesters hnRNP U and thus decreases the level of β-catenin protein via the β-TrCP ubiquitin-degradation pathway. The anti-metastatic effect of GAS7C overexpression was also confirmed using lung cancer xenografts. Our clinical data indicated that 23.6% (25/106) of lung cancer patients showed low expression of GAS7C mRNA which correlated with a poorer overall survival. In addition, low GAS7C mRNA expression was detected in 60.0% of metastatic lung cancer patients, indicating an association between low GAS7C expression and cancer progression. A significant inverse correlation between mRNA expression and promoter hypermethylation was also found, which suggests that the low level of GAS7C expression was partly due to promoter hypermethylation. Our results provide novel evidence that low GAS7C correlates with poor prognosis and promotes metastasis in lung cancer. Low GAS7C increases cancer cell motility by promoting N-WASP/FAK/F-actin cytoskeleton dynamics. It also enhances β-catenin stability via hnRNP U/β-TrCP complex formation. Therefore, GAS7C acts as a metastasis suppressor in lung cancer.

Scott KA, Dennis JL, Dalgleish AG, Liu WM
Inhibiting Heat Shock Proteins Can Potentiate the Cytotoxic Effect of Cannabidiol in Human Glioma Cells.
Anticancer Res. 2015; 35(11):5827-37 [PubMed] Related Publications
Cannabinoids possess a number of characteristics that make them putative anticancer drugs, and their value as such is currently being explored in a number of clinical studies. To further understand the roles that cannabinoids may have, we performed gene expression profiling in glioma cell lines cultured with cannabidiol (CBD) and/or Δ9-tetrahydrocannabinol (THC), and pursued targets identified by this screening. Results showed that a large number of genes belonging to the heat shock protein (HSP) super-family were up-regulated following treatment, specifically with CBD. Increases were observed both at the gene and protein levels and arose as a consequence of increased generation of ROS by CBD, and correlated with an increase in a number of HSP client proteins. Furthermore, increases impeded the cytotoxic effect of CBD; an effect that was improved by co-culture with pharmacalogical inhibitors of HSPs. Similarly, culturing glioma cells with CBD and HSP inhibitors increased radiosensitivity when compared to CBD-alone. Taken together, these data indicate that the cytotoxic effects of CBD can be diminished by HSPs that indirectly rise as a result of CBD use, and that the inclusion of HSP inhibitors in CBD treatment regimens can enhance the overall effect.

Staiano RI, Loffredo S, Borriello F, et al.
Human lung-resident macrophages express CB1 and CB2 receptors whose activation inhibits the release of angiogenic and lymphangiogenic factors.
J Leukoc Biol. 2016; 99(4):531-40 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Macrophages are pivotal effector cells in immune responses and tissue remodeling by producing a wide spectrum of mediators, including angiogenic and lymphangiogenic factors. Activation of cannabinoid receptor types 1 and 2 has been suggested as a new strategy to modulate angiogenesis in vitro and in vivo. We investigated whether human lung-resident macrophages express a complete endocannabinoid system by assessing their production of endocannabinoids and expression of cannabinoid receptors. Unstimulated human lung macrophage produce 2-arachidonoylglycerol,N-arachidonoyl-ethanolamine,N-palmitoyl-ethanolamine, and N-oleoyl-ethanolamine. On LPS stimulation, human lung macrophages selectively synthesize 2-arachidonoylglycerol in a calcium-dependent manner. Human lung macrophages express cannabinoid receptor types 1 and 2, and their activation induces ERK1/2 phosphorylation and reactive oxygen species generation. Cannabinoid receptor activation by the specific synthetic agonists ACEA and JWH-133 (but not the endogenous agonist 2-arachidonoylglycerol) markedly inhibits LPS-induced production of vascular endothelial growth factor-A, vascular endothelial growth factor-C, and angiopoietins and modestly affects IL-6 secretion. No significant modulation of TNF-α or IL-8/CXCL8 release was observed. The production of vascular endothelial growth factor-A by human monocyte-derived macrophages is not modulated by activation of cannabinoid receptor types 1 and 2. Given the prominent role of macrophage-assisted vascular remodeling in many tumors, we identified the expression of cannabinoid receptors in lung cancer-associated macrophages. Our results demonstrate that cannabinoid receptor activation selectively inhibits the release of angiogenic and lymphangiogenic factors from human lung macrophage but not from monocyte-derived macrophages. Activation of cannabinoid receptors on tissue-resident macrophages might be a novel strategy to modulate macrophage-assisted vascular remodeling in cancer and chronic inflammation.

Ziv-Av A, Giladi ND, Lee HK, et al.
RTVP-1 regulates glioma cell migration and invasion via interaction with N-WASP and hnRNPK.
Oncotarget. 2015; 6(23):19826-40 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Glioblastoma (GBM) are characterized by increased invasion into the surrounding normal brain tissue. RTVP-1 is highly expressed in GBM and regulates the migration and invasion of glioma cells. To further study RTVP-1 effects we performed a pull-down assay using His-tagged RTVP-1 followed by mass spectrometry and found that RTVP-1 was associated with the actin polymerization regulator, N-WASP. This association was further validated by co-immunoprecipitation and FRET analysis. We found that RTVP-1 increased cell spreading, migration and invasion and these effects were at least partly mediated by N-WASP. Another protein which was found by the pull-down assay to interact with RTVP-1 is hnRNPK. This protein has been recently reported to associate with and to inhibit the effect of N-WASP on cell spreading. hnRNPK decreased cell migration, spreading and invasion in glioma cells. Using co-immunoprecipitation we validated the interactions of hnRNPK with N-WASP and RTVP-1 in glioma cells. In addition, we found that overexpression of RTVP-1 decreased the association of N-WASP and hnRNPK. In summary, we report that RTVP-1 regulates glioma cell spreading, migration and invasion and that these effects are mediated via interaction with N-WASP and by interfering with the inhibitory effect of hnRNPK on the function of this protein.

Wierzbicki PM, Kogut-Wierzbicka M, Ruczynski J, et al.
Protein and siRNA delivery by transportan and transportan 10 into colorectal cancer cell lines.
Folia Histochem Cytobiol. 2014; 52(4):270-80 [PubMed] Related Publications
INTRODUCTION: Cell penetrating peptides (CPPs) have the ability to translocate through cell membranes with high efficiency and therefore can introduce biological agents with pharmaceutical properties into the cell. Transportan (TP) and its shorter analog transportan 10 (TP10) are among the best studied CPPs, however, their effects on viability of and cargo introduction into colorectal cancer (CRC) cells have yet not been investigated. The aim of our study was to evaluate the cytotoxic effects of TP and TP10 on representative CRC lines and the efficiency of protein (streptavidin) and siRNA cargo delivery by TP-biotinylated derivatives (TP-biot).
MATERIAL AND METHODS: HT29 (early stage CRC model) and HCT116 (metastatic CRC model) cell lines were incubated with TP, TP10, TP-biot1, TP-biot13 and TP10-biot1. The effects of studied CPPs on cell viability and cell cycle were assessed by MTT and annexin V assays. The uptake of streptavidin-FITC complex into cells was determined by flow cytometry and fluorescence microscopy, with the inhibition of cellular vesicle trafficking by brefeldin A. The efficiency of siRNA for SASH1 gene delivery was measured by quantitative PCR (qPCR).
RESULTS: Since up to 10 µM concentrations of each CPP showed no significant cytotoxic effect, the concentrations of 0.5-5 µM were used for further analyses. Within this concentration range none of the studied CPPs affected cell viability and cell cycle. The efficient and endocytosis-independent introduction of streptavidin-FITC complex into cells was observed for TP10-biot1 and TP-biot1 with the cytoplasmic location of the fluorescent cargo; decreased SASH1 mRNA level was noticed with the use of siRNA and analyzed CPPs.
CONCLUSIONS: We conclude that TP, TP10 and their biotinylated derivatives can be used as efficient delivery vehicles of small and large cargoes into CRC cells.

Takeda S, Ikeda E, Su S, et al.
Δ(9)-THC modulation of fatty acid 2-hydroxylase (FA2H) gene expression: possible involvement of induced levels of PPARα in MDA-MB-231 breast cancer cells.
Toxicology. 2014; 326:18-24 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
We recently reported that Δ(9)-tetrahydrocannabinol (Δ(9)-THC), a major cannabinoid component in Cannabis Sativa (marijuana), significantly stimulated the expression of fatty acid 2-hydroxylase (FA2H) in human breast cancer MDA-MB-231 cells. Peroxisome proliferator-activated receptor α (PPARα) was previously implicated in this induction. However, the mechanisms mediating this induction have not been elucidated in detail. We performed a DNA microarray analysis of Δ(9)-THC-treated samples and showed the selective up-regulation of the PPARα isoform coupled with the induction of FA2H over the other isoforms (β and γ). Δ(9)-THC itself had no binding/activation potential to/on PPARα, and palmitic acid (PA), a PPARα ligand, exhibited no stimulatory effects on FA2H in MDA-MB-231 cells; thus, we hypothesized that the levels of PPARα induced were involved in the Δ(9)-THC-mediated increase in FA2H. In support of this hypothesis, we herein demonstrated that; (i) Δ(9)-THC activated the basal transcriptional activity of PPARα in a concentration-dependent manner, (ii) the concomitant up-regulation of PPARα/FA2H was caused by Δ(9)-THC, (iii) PA could activate PPARα after the PPARα expression plasmid was introduced, and (iv) the Δ(9)-THC-induced up-regulation of FA2H was further stimulated by the co-treatment with L-663,536 (a known PPARα inducer). Taken together, these results support the concept that the induced levels of PPARα may be involved in the Δ(9)-THC up-regulation of FA2H in MDA-MB-231 cells.

Liu GH, Chen J, Ji ZG, Zhou L
Expression of Neural Wiskott-Aldrich Syndrome Protein in Clear Cell Renal Cell Carcinoma and Its Correlation with Clinicopathological Features.
Urol Int. 2015; 95(1):79-85 [PubMed] Related Publications
INTRODUCTION: Neural Wiskott-Aldrich syndrome protein (N-WASP) expression is associated with tumor cell invasion and migration. However, its expression status in clear cell renal cell carcinoma (CCRCC) remains unclear. We examined the level of N-WASP in CCRCC and its association with clinicopathological features characteristic.
MATERIALS AND METHODS: 73 CCRCC patients who underwent radical nephrectomy or partial nephrectomy were enrolled. Immunohistochemical staining for N-WASP was performed on tissue microarrays constructed from tumor and para-tumor tissue obtained from these patients. The difference in N-WASP expression between tumor tissue and adjacent normal renal tissue was examined. Correlations between N-WASP expression in the tumor and clinicopathological parameters were analyzed and the relationship between N-WASP expression and overall survival also assessed. Uni- and multivariate survival analyses were performed.
RESULTS: N-WASP expression was significantly reduced in tumor tissues and was significantly related to the histological grade of CCRCC. A higher level of N-WASP expression in the tumor was associated with relatively poor survival in CCRCC patients. The level of N-WASP expression, age at time of surgery, and histological grade were all responsible for clinical outcome in CCRCC patients. N-WASP was an independent predictor for overall survival.
CONCLUSIONS: N-WASP was downregulated in CCRCC and could serve as a prognostic biomarker for predicting clinical outcome of CCRCC.

Moreno E, Andradas C, Medrano M, et al.
Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling.
J Biol Chem. 2014; 289(32):21960-72 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The G protein-coupled receptors CB2 (CB2R) and GPR55 are overexpressed in cancer cells and human tumors. Because a modulation of GPR55 activity by cannabinoids has been suggested, we analyzed whether this receptor participates in cannabinoid effects on cancer cells. Here we show that CB2R and GPR55 form heteromers in cancer cells, that these structures possess unique signaling properties, and that modulation of these heteromers can modify the antitumoral activity of cannabinoids in vivo. These findings unveil the existence of previously unknown signaling platforms that help explain the complex behavior of cannabinoids and may constitute new targets for therapeutic intervention in oncology.

Jia S, Jia Y, Weeks HP, et al.
Down-regulation of WAVE2, WASP family verprolin-homologous protein 2, in gastric cancer indicates lymph node metastasis and cell migration.
Anticancer Res. 2014; 34(5):2185-94 [PubMed] Related Publications
BACKGROUND: WAVE2 plays a crucial role in actin polymerisation and cell migration. We aimed to investigate the expression and cellular functions of WAVE2 in human gastric cancer (GC).
MATERIALS AND METHODS: The level of WAVE2 was determined using quantitative PCR (Q-PCR) in a cohort of human gastric tissues. Expression of WAVE2, ARP2, NWASP, ROCK1 and ROCK2 was examined using RT-PCR in paired tissues. WAVE2 and ARP2 protein co-expression was examined. Anti-WAVE2 transgene ribozymes were constructed and transiently transfected into human GC cells.
RESULTS: Down-regulation of WAVE2 expression in GC was significantly correlated with lymph node metastasis. WAVE2 was positively correlated with E-cadherin and negatively with TWIST. Immunohistochemically, WAVE2 and ARP2 were not co-expressed in serial mirror sections. In vitro, WAVE2 knockdown was shown to increase cell motility, whilst ROCK inhibitor treatment reduced this effect in HGC27 cells.
CONCLUSION: WAVE2 is down-regulated in GC and loses its metastatic role in GC. Knockdown of WAVE2 could increase metastatic potential by promoting the growth, invasiveness, motility, adhesiveness and suppressing EMT (epithelial-mesenchymal transition) of GC cells.

Braun CJ, Boztug K, Paruzynski A, et al.
Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity.
Sci Transl Med. 2014; 6(227):227ra33 [PubMed] Related Publications
Wiskott-Aldrich syndrome (WAS) is characterized by microthrombocytopenia, immunodeficiency, autoimmunity, and susceptibility to malignancies. In our hematopoietic stem cell gene therapy (GT) trial using a γ-retroviral vector, 9 of 10 patients showed sustained engraftment and correction of WAS protein (WASP) expression in lymphoid and myeloid cells and platelets. GT resulted in partial or complete resolution of immunodeficiency, autoimmunity, and bleeding diathesis. Analysis of retroviral insertion sites revealed >140,000 unambiguous integration sites and a polyclonal pattern of hematopoiesis in all patients early after GT. Seven patients developed acute leukemia [one acute myeloid leukemia (AML), four T cell acute lymphoblastic leukemia (T-ALL), and two primary T-ALL with secondary AML associated with a dominant clone with vector integration at the LMO2 (six T-ALL), MDS1 (two AML), or MN1 (one AML) locus]. Cytogenetic analysis revealed additional genetic alterations such as chromosomal translocations. This study shows that hematopoietic stem cell GT for WAS is feasible and effective, but the use of γ-retroviral vectors is associated with a substantial risk of leukemogenesis.

Bidad K, Nawijn MC, van Oosterhout AJ, et al.
Basophil activation test in the diagnosis and monitoring of mastocytosis patients with wasp venom allergy on immunotherapy.
Cytometry B Clin Cytom. 2014; 86(3):183-90 [PubMed] Related Publications
BACKGROUND: There is need for an accurate diagnostic test in mastocytosis patients with wasp venom allergy (WVA) and monitoring of these patients during immunotherapy (IT). In this study, we aimed to evaluate sensitivity and specificity of the Basophil Activation Test (BAT) as a diagnostic and monitoring test in patients with mastocytosis and WVA.
METHODS: Seventeen patients with mastocytosis and WVA and six mastocytosis patients without WVA were included. BAT was performed before the start of IT (first visit) and at 6 weeks (second visit) and 1 year (third visit), after reaching the maintenance dose. Of 17 patients included, 11 completed the third visit. In mastocytosis patients with WVA, dose-dependent wasp-venom induced upregulation of CD63 and CD203c expression on basophils was observed compared with mastocytosis patients without WVA. Serum specific IgE, IgG4, and tryptase levels were measured in all patients.
RESULTS: BAT had a sensitivity of 87% and specificity of 100% in diagnosing WVA in mastocytosis patients. Basophil allergen threshold sensitivity with respect to CD63 and CD203c was significantly decreased in the second visit compared with the first visit and increased significantly in the third visit compared with the second visit. Specific IgE levels increased significantly in the second visit compared with first and decreased significantly in the third visit compared with the second. Specific IgG4 levels rose significantly in the second visit compared with the first and on the third visit compared with the second. Tryptase levels did not change significantly during the study.
CONCLUSIONS: BAT represents a diagnostic test with 100% specificity in allergic patients with mastocytosis and these patients are better to be monitored for a longer period during IT.

Emery SM, Alotaibi MR, Tao Q, et al.
Combined antiproliferative effects of the aminoalkylindole WIN55,212-2 and radiation in breast cancer cells.
J Pharmacol Exp Ther. 2014; 348(2):293-302 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
The potential antitumor activity of cannabinoid receptor agonists, such as the aminoalklylindole WIN55,212-2 (WIN2), has been studied extensively, but their potential interaction with conventional cancer therapies, such as radiation, remains unknown. In the present work, the influence of WIN2 on the antiproliferative activity of radiation in human (MCF-7 and MDA-MB231) and murine (4T1) breast cancer cells was investigated. The antiproliferative effects produced by combination of WIN2 and radiation were more effective than either agent alone. The stereoisomer of WIN2, WIN55,212-3 (WIN3), failed to inhibit growth or potentiate the growth-inhibitory effects of radiation, indicative of stereospecificity. Two other aminoalkylindoles, pravadoline and JWH-015 [(2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenyl-methanone], also enhanced the antiproliferative effects of radiation, but other synthetic cannabinoids (i.e., nabilone, CP55,940 [(+)-rel-5-(1,1-dimethylheptyl)-2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-phenol], and methanandamide) or phytocannabinoids [i.e., Δ⁹-tetrahydrocannabinol (THC) and cannabidiol] did not. The combination treatment of WIN2 + radiation promoted both autophagy and senescence but not apoptosis or necrosis. WIN2 also failed to alter radiation-induced DNA damage or the apparent rate of DNA repair. Although the antiproliferative actions of WIN2 were mediated through noncannabinoid receptor-mediated pathways, the observation that WIN2 interfered with growth stimulation by sphingosine-1-phosphate (S1P) implicates the potential involvement of S1P/ceramide signaling pathways. In addition to demonstrating that aminoalkylindole compounds could potentially augment the effectiveness of radiation treatment in breast cancer, the present study suggests that THC and nabilone are unlikely to interfere with the effectiveness of radiation therapy, which is of particular relevance to patients using cannabinoid-based drugs to ameliorate the toxicity of cancer therapies.

Tang Z, Araysi LM, Fathallah-Shaykh HM
c-Src and neural Wiskott-Aldrich syndrome protein (N-WASP) promote low oxygen-induced accelerated brain invasion by gliomas.
PLoS One. 2013; 8(9):e75436 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Malignant gliomas remain associated with poor prognosis and high morbidity because of their ability to invade the brain; furthermore, human gliomas exhibit a phenotype of accelerated brain invasion in response to anti-angiogenic drugs. Here, we study 8 human glioblastoma cell lines; U251, U87, D54 and LN229 show accelerated motility in low ambient oxygen. Src inhibition by Dasatinib abrogates this phenotype. Molecular discovery and validation studies evaluate 46 molecules related to motility or the src pathway in U251 cells. Demanding that the molecular changes induced by low ambient oxygen are reversed by Dasatinib in U251 cells, identifies neural Wiskott-Aldrich syndrome protein (NWASP), Focal adhesion Kinase (FAK), [Formula: see text]-Catenin, and Cofilin. However, only Src-mediated NWASP phosphorylation distinguishes the four cell lines that exhibit enhanced motility in low ambient oxygen. Downregulating c-Src or NWASP by RNA interference abrogates the low-oxygen-induced enhancement in motility by in vitro assays and in organotypic brain slice cultures. The findings support the idea that c-Src and NWASP play key roles in mediating the molecular pathogenesis of low oxygen-induced accelerated brain invasion by gliomas.

Malet-Engra G, Viaud J, Ysebaert L, et al.
CIP4 controls CCL19-driven cell steering and chemotaxis in chronic lymphocytic leukemia.
Cancer Res. 2013; 73(11):3412-24 [PubMed] Related Publications
Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of nonsolid tumors such as leukemia depends on the deregulated expression of molecules decoding chemotactic signals remains an open question. We identify here the membrane remodeling F-BAR adapter protein Cdc42-interacting protein 4 (CIP4) as a key regulator of chemotaxis in chronic lymphocytic leukemia (CLL). CIP4 is expressed at abnormally high levels in CLL cells, where it is required for CCL19-induced chemotaxis. Upon CCL19 stimulation of CLL cells, CIP4 associates with GTP-bound Cdc42 and is recruited to the rear of the lamellipodium and along microspikes radiating through the lamellipodium. Consistent with its cellular distribution, CIP4 removal impairs both the assembly of the polarized lamellipodium and directional migration along a diffusible CCL19 gradient. Furthermore, CIP4 depletion results in decreased activation of WASP, but increased activation of PAK1 and p38 mitogen-activated protein kinase (MAPK). Notably, p38 MAPK inhibition results in impaired lamellipodium assembly and loss of directional migration. This suggests that CIP4 modulates both the WASP and p38 MAPK pathways to promote lamellipodium assembly and chemotaxis. Overall, our study reveals a critical role of CIP4 in mediating chemotaxis of CLL cells by controlling the dynamics of microspike-containing protrusions and cell steering.

Ghosh D, Li Z, Tan XF, et al.
iTRAQ based quantitative proteomics approach validated the role of calcyclin binding protein (CacyBP) in promoting colorectal cancer metastasis.
Mol Cell Proteomics. 2013; 12(7):1865-80 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
Keeping continuity with our previous study that revealed direct correlations between CRC metastasis and enhanced CacyBP protein levels, here we attempt to improve our understanding of the mechanisms involved within this enigmatic process. Overexpression of CacyBP (CacyBP-OE) in primary CRC cell and its knock down (CacyBP-KD) in the metastatic CRC cells revealed (through phenotypic studies) the positive impact of the protein on metastasis. Additionally, two individual 4-plex iTRAQ based comparative proteomics experiments were carried out on the CacyBP-OE and CacyBP-KD cells, each with two biological replicates. Mining of proteomics data identified total 279 (63.80% up-regulated and 36.20% down-regulated) proteins to be significantly altered in expression level for the OE set and in the KD set, this number was 328 (48.78% up-regulated and 51.22% down-regulated). Functional implications of these significantly regulated proteins were related to metastatic phenotypes such as cell migration, invasion, adhesion and proliferation. Gene ontology analysis identified integrin signaling as the topmost network regulated within CacyBP-OE. Further detection of caveolar mediated endocytosis in the top hit list correlated this phenomenon with the dissociation of integrins from the focal adhesion complex which are known to provide the traction force for cell movement when transported back to the leading edge. This finding was further supported by the data obtained from CacyBP-KD data set showing down-regulation of proteins necessary for integrin endocytosis. Furthermore, intracellular calcium levels (known to influence integrin mediated cell migration) were found to be lowered in CacyBP-KD cells indicating decreased cell motility and vice versa for the CacyBP-OE cells. Actin nucleation by ARP-WASP complex, known to promote cell migration, was also identified as one of the top regulated pathways in CacyBP-OE cells. In short, this study presents CacyBP as a promising candidate biomarker for CRC metastasis and also sheds light on the underlying molecular mechanism by which CacyBP promotes CRC metastasis.

Takeda S, Harada M, Su S, et al.
Induction of the fatty acid 2-hydroxylase (FA2H) gene by Δ(9)-tetrahydrocannabinol in human breast cancer cells.
J Toxicol Sci. 2013; 38(2):305-8 [PubMed] Article available free on PMC after 01/04/2017 Related Publications
To investigate gene(s) being regulated by ∆(9)-tetrahydrocannabinol (∆(9)-THC), we performed DNA microarray analysis of human breast cancer MDA-MB-231 cells, which are poorly differentiated breast cancer cells, treated with ∆(9)-THC for 48 hr at an IC50 concentration of approximately 25 µM. Among the highly up-regulated genes (> 10-fold) observed, fatty acid 2-hydroxylase (FA2H) was significantly induced (17.8-fold). Although the physiological role of FA2H has not yet been fully understood, FA2H has been shown to modulate cell differentiation. The results of Oil Red O staining after ∆(9)-THC exposure showed the distribution of lipid droplets (a sign of the differentiated phenotype) in cells. Taken together, the results obtained here indicate that FA2H is a novel ∆(9)-THC-regulated gene, and that ∆(9)-THC induces differentiation signal(s) in poorly differentiated MDA-MB-231 cells.

Tang H, Li A, Bi J, et al.
Loss of Scar/WAVE complex promotes N-WASP- and FAK-dependent invasion.
Curr Biol. 2013; 23(2):107-17 [PubMed] Related Publications
BACKGROUND: The Scar/WAVE regulatory complex (WRC) drives lamellipodia assembly via the Arp2/3 complex, whereas the Arp2/3 activator N-WASP is not essential for 2D migration but is increasingly implicated in 3D invasion. It is becoming ever more apparent that 2D and 3D migration utilize the actin cytoskeletal machinery differently.
RESULTS: We discovered that WRC and N-WASP play opposing roles in 3D epithelial cell migration. WRC depletion promoted N-WASP/Arp2/3 complex activation and recruitment to leading invasive edges and increased invasion. WRC disruption also altered focal adhesion dynamics and drove FAK activation at leading invasive edges. We observed coalescence of focal adhesion components together with N-WASP and Arp2/3 complex at leading invasive edges in 3D. Unexpectedly, WRC disruption also promoted FAK-dependent cell transformation and tumor growth in vivo.
CONCLUSIONS: N-WASP has a crucial proinvasive role in driving Arp2/3 complex-mediated actin assembly in cooperation with FAK at invasive cell edges, but WRC depletion can promote 3D cell motility.

Jin KM, Lu M, Liu FF, et al.
N-WASP is highly expressed in hepatocellular carcinoma and associated with poor prognosis.
Surgery. 2013; 153(4):518-25 [PubMed] Related Publications
BACKGROUND: Neural Wiskott-Aldrich syndrome protein (N-WASP) mediates migration and invasion in cancer cells, but its expression and clinicopathologic and prognostic importance in hepatocellular carcinoma (HCC) remain unknown. The present study was designed to address these issues.
METHODS: N-WASP expression was first analyzed by Western blotting in 19 paired HCC and paratumoral liver (PTL) tissues. We further evaluated N-WASP expression immunohistochemically in samples from 119 patients with HCC. The clinicopathologic and prognostic importance of N-WASP expression were also investigated.
RESULTS: Western blotting showed that N-WASP expression was up-regulated in 15 of 19 HCC tissues (79%), compared with PTL ones. The N-WASP-positive rate in immunohistochemical staining also was greater in HCC (63/119, 53%) than that in PTL tissues (8/119, 6%). The up-regulated N-WASP expression in HCC tissues was correlated with absence of capsule formation and predicted less overall and disease-free survival. Multivariate analysis demonstrated that N-WASP was an independent prognostic factor for overall survival and was marginally important for disease-free survival.
CONCLUSION: These data establish that N-WASP is highly expressed in HCC and its strong prognostic importance. Therefore, the gene/protein might serve as a potential therapeutic target for HCC.

Yoshimi A, Kamachi Y, Imai K, et al.
Wiskott-Aldrich syndrome presenting with a clinical picture mimicking juvenile myelomonocytic leukaemia.
Pediatr Blood Cancer. 2013; 60(5):836-41 [PubMed] Related Publications
BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency caused by defects of the WAS protein (WASP) gene. Patients with WAS typically demonstrate micro-thrombocytopenia.
PROCEDURES: The report describes seven male infants with WAS that initially presented with leukocytosis, monocytosis, and myeloid and erythroid precursors in the peripheral blood (PB) and dysplasia in the bone marrow (BM), which was initially indistinguishable from juvenile myelomonocytic leukaemia (JMML).
RESULTS: The median age of affected patients was 1 month (range, 1-4 months). Splenomegaly was absent in four of these patients, which was unusual for JMML. A mutation analysis of genes in the RAS-signalling pathway did not support a diagnosis of JMML. Non-haematological features, such as eczema (n = 7) and bloody stools (n = 6), ultimately led to the diagnosis of WAS at a median age of 4 months (range, 3-8 months), which was confirmed by absent (n = 6) or reduced (n = 1) WASP expression in lymphocytes by flow cytometry (FCM) and a WASP gene mutation. Interestingly, mean platelet volume (MPV) was normal in three of five patients and six of seven patients demonstrated occasional giant platelets, which was not compatible with WAS.
CONCLUSIONS: These data suggest that WAS should be considered in male infants presenting with JMML-like features if no molecular markers of JMML can be detected.

Sano H, Kobayashi R, Suzuki D, et al.
Wiskott-Aldrich syndrome with unusual clinical features similar to juvenile myelomonocytic leukemia.
Int J Hematol. 2012; 96(2):279-83 [PubMed] Related Publications
A male infant exhibited thrombocytopenia at birth, and later developed leukocytosis, monocytosis, and bloody stool. The bone marrow was hypercellular with dysplasia. Spontaneous granulocyte/macrophage-colony formation and hypersensitivity to granulocyte/macrophage-colony stimulating factor were confirmed by in vitro culture. These findings fulfilled most of the diagnostic criteria for juvenile myelomonocytic leukemia (JMML), with the exception of splenomegaly. However, no mutations in the PTPN11, RAS, and CBL genes, or clinical features of neurofibromatosis type 1, which are associated with JMML, were detected. The patient subsequently developed refractory eczema with undetectable serum IgM, which led to the consideration of Wiskott-Aldrich syndrome (WAS). Lack of WASP expression and a 4-nucleotide deletion mutation in WASP were identified. Approximately 20 % of patients with JMML show none of the abovementioned molecular abnormalities. Careful differential diagnosis, including the consideration of WAS, is, therefore, recommended in patients with clinical features and laboratory findings consistent with JMML.

Thapa D, Kang Y, Park PH, et al.
Anti-tumor activity of the novel hexahydrocannabinol analog LYR-8 in Human colorectal tumor xenograft is mediated through the inhibition of Akt and hypoxia-inducible factor-1α activation.
Biol Pharm Bull. 2012; 35(6):924-32 [PubMed] Related Publications
Cannabinoid compounds have been shown to exert anti-tumor effects by affecting angiogenesis, invasion, and metastasis. In the present study, we examined the action mechanism by which LYR-8, a novel hexahydrocannabinol analog, exerts anti-angiogenic and anti-tumor activity in human cancer xenografts. In the xenografted tumor tissues, LYR-8 significantly reduced the expression of hypoxia-inducible factor-1 alpha (HIF-1α), a transcription factor responsible for induction of angiogenesis-promoting factors, and its target genes, vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). In HT-29 human colon cancer cells treated with a hypoxia-inducing agent (CoCl(2)), LYR-8 dose-dependently suppressed the induction of HIF-1α and subsequently its targets, VEGF and COX-2. In addition, highly elevated prostaglandin E(2) (PGE(2)) concentrations in CoCl(2)-treated HT-29 cells were also significantly suppressed by LYR-8. However, LYR-8 alone in the absence of CoCl(2) did not alter the basal expression of VEGF and COX-2, or PGE(2) production. Furthermore, LYR-8 effectively suppressed Akt signaling, which corresponded to the suppression of CoCl(2)-induced HIF-1α accumulation. Taken together, LYR-8 exerts anti-tumor effects through the inhibition of Akt and HIF-1α activation, and subsequently suppressing factors regulating tumor microenvironment, such as VEGF and COX-2. These results indicate a novel function of cannabinoid-like compound LYR-8 as an anti-tumor agent with a HIF-1α inhibitory activity.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. WAS, Cancer Genetics Web: http://www.cancer-genetics.org/WAS.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 13 March, 2017     Cancer Genetics Web, Established 1999