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Wid 0 eseupt euje}cucl ciu ewomqouRei wdi c:ppm iod segõelos NdVS „eseuN u!elaid sseils„ 38S leia} ou!noq aos dNS olloos ep ole!ssrucloilp dYNS sumello!ued peoe-N oso4u-s ANl “Joloej. s!soneu Jown1„ )INr „eseups 'simula; unr„ ON eseqoiN CPI uoliePolP1 7idV1/4 aeseupi u!epid pewApe-ue6cmw„ lAlw Jelowww wu soilew9weu ON oopiju opxo C6lulas epiteliais, endoteliais e fibroblastos podem ser induzidas a apoptose (anoikis) quando se destacam da matriz extracelular. O processo de anoikis tem a função de proteger o organismo da colonização inapropriada destas células. O processo de apoptose pode ser induzido por vhrios estímulos, dentre eles, o óxido nitrico (NO). O radical livre NO pode ser sintetizado em organismos vivos pela ação das enzimas NO sintases (NOS), como tambem pode ser liberado por compostos doadores de NO. A geração intracelular ou extracelular de NO pode resultar em diferenciago, proliferação ou morte celular, dependendo da natureza e quantidades de NO gerado no processo, como tambem do tipo de celular alvo da ação do radical livre. Este trabalho estudou a induçáo do processo de apoptose iniciada pelo doador de óxido nítriw nitroprussiato de sódio (SNP) em células de linhagem células A431 de carcinoma epiderrnóide humano. A partir de 6 horas de tratamento com SNP ImM, as células destacadas já estgo positivas para citoqueratina 18 (CK18), anexina-V e apresentam caspases 3 e 8 ativas. Elevado conteúdo de bax e queda de bcl-2, representando uma razão bcl-2lbax compatível com apoptose é alcançada após 24 horas de tratamento com SNP 1mM, bem como ativação de JNK, reação de Tunnel viii positivo, positividade ao corante Hoescht 33258, atividade insignificante de LD, marcação positiva para anexina-V e negativa para iodeto de propídio (PI>. As propriedades antiadesivas do NO foram observadas analisando-se o aumento da perda de aderencia e diminuição de viabilidade das células destacadas após tratamento wrn SNP e positividade para anticorpo anti- citoqueratina AE1 e AE2. Cblulas plaqueadas em diferentes superfícies que dificultam o processo de aderencia, quando submetidas ao tratamento com SNP rompem mais facilmente os complexos de adesão e se destacam mais rapidamente. Os resultados apresentados sugerem que o NO promove alterações na integridade do citoesqueleto, que induzem as células A431 à apoptose por perda de aderencia a matriz extracelular. ABSTRACT Epithelial cells, endotelial cells, and fibroblasts undergo a special kind of apoptosis (anoikis) that occurs when they are displaced from the extracellular matriz. Anoikis is thought to protect tissues from inappropriate colonization. A number of studies described apoptogenic and anti-apoptotic properties for nitric oxide (NO). Our studies focused on the induced apoptosis of the human epithelial carcinoma cell line A431 after exposure to an NO donor, sodium nitroprusside. Initially, the following features were associated with NO-induced A431 cell death: decreased expression of Bcl-2, enhanced expression of Bax, and activation of the stress related MAP kinase, JNK. In addition, NO treated cells were positive for the TUNEL assay, and for Hoescht 33258 staining. Caspase 8 and 3 activities was detected in the system. Continuing our investigation on the mechanisms ori the underlying the NO-induced apoptosis, we investigated modifications on the cytoskeleton upon exposure of A431 cells to the NO donor. NO presents anti-adhesive properties, either down regulating the expression of adhesion molecules or disrupting adhesion complexes. Accordingly, we found that A431 cells undergoing NO-induced apoptosis (positive for Anexin V labeling and negative for propidiurn iodide labeling), featured a loss of cytoskeleton integrity, and an insufíicient rescue of the supernatant cells. In conclusion, our findings suggest that NO promote the adhesion related apoptosis, anoikis, in A431 cells. ov5naoaiNi- I. 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"le "r •a `)Ped)saua6 savo JeMeS1184 aled apepifidet4 wes sew ossaidxa opuas `(9961, "ie ;e "3 innopeH) eupp.s!Li ewn Jod epeoo4 !oj eu!u!ffie ewn apuo '(9,HgLz) gLE uopoo ou owbeinw ewn ewasaide ggd aue6 o `s!od gieiniao opto o W 00 £gd ap oessaidxa oç5npailui SOALLWEIO - I Et sopoleinj e SIBialen we epeuoioeiei e!Bolopmew ela' sepepnlse weio4 sele agua owbelei e a osseowd oppapJ o woo sepeuopelai seuie4oJd sep epepme ep esneue kr (spfioue) Jelnieoeipce zplew e oesepe ep eped iod epepu! `1.£17V ouewnli ap!owiep!de ewoupeo ep we6equ!! ep seinleo wa asoldode Aznpui leo!pal op ase494 e es-nopn}se Son!sepeRue sol!eA inssod anb e saielniao soda} sun6ie we esoldode ep Jo4npui a ON o enb es-opueiap!suop sonnercio SOC1013IN 3 SIVIt131VIAI — e çt7 woo opue;uawaidns l (-!i8-ooqe) n3isa-s c000aqina Jod opeowpow al6e3 o!aw we epemino 10j. 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'opgiluoo oe !ogsape ap epied JeAet eied aluepos !oa ogu dNS ap LAJW9`0 ap ogSeiluaoucio v -ole4sqns oe ()pape ap epied ens e awawaluepwoouoo seiniço sep ePow e ipa6ns sou-waquued sopelinsai sas3 .eu!s!lliod logsape ap emssmied ogu epjpedns eu sepeawas seno° seu oN op s!epue;sqns sol!ap wenemasqo as ogu sew `oN ap Jopeop oiad awawiepueisqns oppnpui loa oue6gioo wequ000 anb seoeid sep seinpo sep olueweoe;sep o •owawele4 was apiwoo eoeid ep ç aluegiawas Oolopow wequg oua6gioo we sepeenbeid se anb ossed oe `epepuopane efflolopow woo as-weJewasaide seiniao se 'eu!smod ap e5uasaid eN 'dNS oe se;sodxa (eu!swiod a oueNco) sazplew salualapp wa sepenno seinieo se 'Jena° ogsape eu oN op og5erne e JeAsuowap aled .owaweleil was saluepeumos seiniço seu opemesqo ogu eu!leienb ap apai eu ofueuesap wn opue4sow `zav a 63v eu!leJanbolpgue odJooRue eied enwsod ogõew weiem e oçssnosia letwou effioppow 86 N31N opuenge '(6661. "ie megsuad) seup6aw! Jod epe!pew minta° °pape e Jein6a, waqwe4 owoo 'mino wa asoldode Aznpu! a (00o2 "le `ol!aiuovsi '9661. "le iisiam-uosseen) selni?0 sewn6le wa oluawpsaio Aci!u! apod 'ON ap salopeop Jod no eugesopue Jod epeinimise Syd ap ow3elpoj.sol V . (6661. 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"le `119140) seseurb dvis sep oe5enge e opuenowoid seu e es-eposse oxeidwoo 91,93 •salopexlepe seu jeloid ap oxeidwoo op oluaweisuom o ufanou:11d led ap oeSeipopojowe e a seup694u! sep oeõenge y -oesape wed sepesseoau eugoe ap seiqgoio!w ap oe,3euuo4 e wen!le 'zan ens iod canb `)1.13 oçssnom 1.0I L £17V se l n I90 We ON Jod ep!znpu! !ol `sppoue+-NNN-sasedseo4-xeci / z-pq <- seup6am '966 1. "18 49 ospd Jod elsodoid owbezmews ap mn e anb Jodaid sowepapod isope4insai sossou wa sopeaseq `w!ssy (sope.ilsow nu sopep) ow5enge ens ap oeSoa4ap e ienissod °puas oçu idNS Ww 1. woo semi] 17z o4uewe4ei4 s9de epinu!wp es-noluasaide 1.g.fry wa opsaidxe efno `(L666 • e 49 uewiews) E-Nd3/6-)1213 -m3vg - vjed -seu) seu eoRoldodeRue eujelcud ep owáenge ap ein B owoo We4Sp(800 Nflf ep 0,q5eARe ? seialeied selo seP9A (LOOZ "l e 49 1PAy) seuq6aw! 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