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ARTICLE IN PRESST.-A. Tran et al. / Biochemical and Biophysical Research Communications xxx (2009\) xxx–xxx 5only when we will have a better understanding of the molecularlink between Na V and invasiveness.AcknowledgmentsWe thank the Université François-Rabelais de Tours for fundingthe visit of EW to Inserm U921. This work was financed in part by agrant from the Ligue Contre le Cancer de la Région Centre.References[1] G. Dang, C. Hudis, Adjuvant taxanes in the treatment of breast cancer: nolonger at the tip of the iceberg, Clin. Breast Cancer 7 (2006) 51–58.[2] S. Horwitz, Taxol (Paclitaxel): mechanisms of action, Ann. Oncol. 5 (1994)S3–S6.[3] J. Camacho, A. Sanchez, W. Stühmer, L. Pardo, Cytoskeletal interactionsdetermine the electrophysiological properties of human EAG potassiumchannels, Pflügers Arch. 441 (2000) 167–174.[4] S. Roger, P. Besson, J.-Y. Le Guennec, Involvement of a novel fast inward sodiumcurrent in the invasion capacity of a breast cancer cell line, Biochim. Biophys.Acta 1616 (2003) 107–111.[5] S. Roger, J. Rollin, A. Barascu, P. Besson, P.-I. Raynal, S. Iochmann, M. Lei, P.Bougnoux, Y. Gruel, J.-Y. Le Guennec, Voltage-gated sodium channelspotentiate the invasive capacities of human non-small-cell lung cancer celllines, Int. J. Biochem. Cell Biol. 39 (2007) 774–786.[6] S. Roger, M. Potier, C. Vandier, P. Besson, J.-Y. Le Guennec, Voltage-gatedsodium channels: new targets for epithelial cancer therapy?, Curr Pharm. Des.12 (2006) 3681–3695.[7] S. Judé, S. Roger, E. Martel, P. Besson, S. Richard, P. Bougnoux, J.-Y. Le Guennec,Dietary long-chain omega-3 fatty acids of marine origin: a comparison of theirprotective effects on coronary heart disease and breast cancers, Prog. Biophys.Mol. Biol. 90 (2006) 299–325.[8] S. Roger, P. Besson, J.-Y. Le Guennec, Influence of the whole cell patch-clampconfiguration on electrophysiological properties of the voltage-dependentsodium current expressed in MDA-MB-231 breast cancer cells, Eur. Biophys. J.33 (2004) 274–279.[9] V. Maltsev, A. Undrovinas, Cytoskeleton modulates coupling betweenavailability and activation of cardiac sodium channel, Am. J. Physiol. 273(1997) H1832–H1840.[10] T. Mosmann, Rapid colorimetric assay for cellular growth and survival:application to proliferation and cytotoxicity assays, J. Immunol. Methods 65(1983) 55–63.[11] H. Tsutsui, K. Ishihara, G. Cooper 4th, Cytoskeletal role in the contractiledysfunction of hypertrophied myocardium, Science 260 (1993) 682–687.[12] M. Takahashi, H. Shiraishi, Y. Ishibashi, K. Blade, P. McDermott, D. Menick, D.Kuppuswamy, G. Cooper IV, Phenotypic consequences of b 1 -tubulin expressionand MAP 4 decoration of microtubules in adult cardiocytes, Am. J. Physiol.Heart Circ. Physiol. 285 (2003) H2072–H2083.[13] U.K. Laemmli, Cleavage of structural proteins during the assembly of the headof bacteriophage T4, Nature 227 (1970) 680–685.[14] S. Fraser, J. Diss, A. Chioni, M. Mycielska, H. Pan, R. Yamaci, F. Pani, Z. Siwy, M.Krasowska, Z. Grzywna, W. Brackenbury, D. Theodorou, M. Koyuturk, H. Kaya,E. Battaloglu, M. De Bella, M. Slade, R. Tolhurst, C. Palmieri, J. Jiang, D.Latchman, R. Coombes, M. Djamgoz, Voltage-gated sodium channel expressionand potentiation of human breast cancer metastasis, Clin. Cancer Res. 11(2005) 5381–5389.[15] D. Motlagh, K. Alden, B. Russell, J. Garcia, Sodium current modulation by atubulin/GTP coupled process in rat neonatal cardiac myocytes, J. Physiol. 540.1(2002) 93–103.Please cite this article in press as: T. -A. Tran et al., Non-anti-mitotic concentrations of taxol reduce breast cancer cell invasiveness, Biochem.Biophys. Res. Commun. (2009), doi:10.1016/j.bbrc.2008.12.073
Oncogene (2008), 1–12& 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00www.nature.com/oncORIGINAL ARTICLEAutotaxin protects MCF-7 breast cancer and MDA-MB-435 melanomacells against Taxol-induced apoptosisN Samadi 1 , C Gaetano 2 , IS Goping 2 and DN Brindley 21Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada and 2 Departmentof Biochemistry (Signal Transduction Research Group), University of Alberta, Edmonton, Alberta, CanadaAutotaxin (ATX) promotes cancer cell survival, growth,migration, invasion and metastasis. ATX converts extracellularlysophosphatidylcholine (LPC) into lysophosphatidate(LPA). As these lipids have been reported toaffect cell signaling through their own G-protein-coupledreceptors, ATX could modify the balance of this signaling.Also, ATX affects cell adhesion independently of its catalyticactivity. We investigated the interactions of ATX,LPC and LPA on the apoptotic effects of Taxol, which iscommonly used in breast cancer treatment. LPC had nosignificant effect on Taxol-induced apoptosis in MCF-7breast cancer cells, which do not secrete significant ATX.Addition of incubation medium from MDA-MB-435melanoma cells, which secrete ATX, or recombinat ATXenabled LPC to inhibit Taxol-induced apoptosis ofMCF-7 cells. Inhibiting ATX activity blocked this protectionagainst apoptosis. We conclude that LPC has nosignificant effect in protecting MCF-7 cells against Taxoltreatment unless it is converted to LPA by ATX. LPAstrongly antagonized Taxol-induced apoptosis throughstimulating phosphatidylinositol 3-kinase and inhibitingceramide formation. LPA also partially reversed theTaxol-induced arrest in the G2/M phase of the cell cycle.Our results support the hypothesis that therapeuticinhibition of ATX activity could improve the efficacy ofTaxol as a chemotherapeutic agent for cancer treatment.Oncogene advance online publication, 15 December 2008;doi:10.1038/onc.2008.442Keywords: ceramides; chemotherapy; chemoresistance;lysophosphatidate; lysophosphatidylcholine; phosphatidylinositol3-kinaseIntroductionCorrespondence:Professor DN Brindley, Department of Biochemistry(Signal Transduction Research Group), University of Alberta,Edmonton, Alberta, Canada T6G 2S2.E-mail:david.brindley@ualberta.caReceived 24 July 2008; revised 8 October 2008; accepted 1 November2008Breast cancer is the most common malignancy amongwomen in North America and approximately one-thirdof these women develop metastases and die (Jemal et al.,2006). Dysregulation of normal mechanisms of apoptosisplay an important role in the pathogenesis andprogression of breast cancer. Importantly, the efficacy ofchemotherapy can be compromised by the survivalsignals that tumor cells receive (Krajewski et al., 1999).There is a strong association of autotaxin (ATX)expression with breast cancer cell survival, growth,migration, invasion and metastasis (Nam et al., 2000,2001; Umezu-Goto et al., 2002; Yang et al., 2002; Hamaet al., 2004). ATX was originally isolated from humanmelanoma A2058 cells (Stracke et al., 1992) and itgenerates lysophosphatidate (LPA) from circulatinglysophosphatidylcholine (LPC). Although the involvementof LPA and ATX in the invasiveness of breastcancer has been studied (Yang et al., 2002), relativelylittle is known about how ATX might confer chemoresistance.First, the substrate of ATX, LPC, hasbeen postulated to be an extracellular signaling lipidby acting on G2A and GPR4 (Kabarowski et al., 2001;Zhu et al., 2001; Rikitake et al., 2002; Lin and Ye, 2003;Radu et al., 2004; Kim et al., 2005). Unsaturated LPC issecreted by the liver (Brindley, 1993) and saturated LPCis produced by circulating lecithin:cholesterol acyltransferasein high-density lipoproteins (Aoki et al.,2002). LPC is present in blood at up to 200 mM(Moolenaar et al., 2004). ATX could, therefore, regulatecell activation through changing signaling by LPCversus LPA. Secondly, ATX decreases the adhesion ofoligodendrocytes to the extracelllular matrix through anon-catalytic mechanism involving its C-terminus, andthis facilitates morphological remodeling (Dennis et al.,2005). This suggests that ATX is a matrix-cellularprotein that signals through integrin-dependent focaladhesion assembly and consequently cell interactionswith the extracellular matrix (Fox et al., 2004). This andother non-catalytic effects of ATX could contribute toits association with the aggressiveness of cancer cells.Autotaxin provides a major route for generatingextracellular LPA, which is present at up to 20 mM inblood and extracellular fluid (Moolenaar et al., 2004;Yue et al., 2004). LPA is produced by activated plateletsto facilitate wound healing and is secreted by cancer cells(Fang et al., 2000; Radeff-Huang et al., 2004). ExtracellularLPA has been implicated in the etiology ofhuman cancer, as it stimulates cell growth, proliferation,differentiation, motility and survival (Mills and Moolenaar,2003; Brindley, 2004). Diverse actions of LPA aremediated by at least six G-protein coupled receptors
Page 2 and 3: 56MethodsCell culture, reagents and
Page 4 and 5: 1314DiscussionThe prognosis of brea
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Page 16 and 17: 4Table 1Taxol(nM)Effect of LPA on T
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