Abstract
Apoptosis pathways in cells are classified into two pathways: the extrinsic pathway, mediated by binding of the ligand to a death receptor and the intrinsic pathway, mediated by mitochondria. Apoptosis is regulated by various proteins such as Bcl-2 (B-cell lymphoma 2) family and cellular FLICE (Fas-associated Death Domain Protein Interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which have been reported to inhibit caspase-8 activity. In this study, it was found that C5 (3β-Acetyl-nor-erythrophlamide), a compound of cassaine diterpene amine from Erythrophleum fordii, induced cell apoptosis in a variety of types of cancer cells. Induction of apoptosis in cancer cells by C5 was inversely related to the level of Bcl-2 expression. Overexpression of Bcl-2 into cancer cells significantly decreased C5-induced apoptosis. It was also found that treatment of cancer cells with a caspase-8 inhibitor significantly suppressed C5-induced apoptosis; however, treatment with caspase-9 inhibitors did not affect C5-induced apoptosis, suggesting that C5 may induce apoptosis via the extrinsic pathway by activating caspase-8. It was confirmed that treatment with C5 alone induced an association of FADD with procaspase-8; however, overexpression of c-FLIP decreased C5-induced caspase-8 activation. In conclusion, C5 could be utilized as a new useful lead compound for the development of an anti-cancer agent that has the goal of apoptosis.
Highlights
Apoptosis is the process of programmed cell death, generally known as morphological and biological modifications, including cell shrinkage, nuclear fragmentation, and membrane blebbing [1,2]
C5 Induces the Formation of DISC without Affecting the Expression of Death Receptor and Death LigaTnodeinvaElxutartienstihceAmpooplteocsuislaPramthewcahyanism of the extrinsic pathway regulated by C5, we investigated the enxothpt eraeffesxTespcoiotreeenvdssoabilfouytnahCtoee5fdttihheneaertmedhseopraleeotchcneurspleeatcorteormpaateontcridhmaadnnede-isdadmtehepaoeltfinhgtdhalineegndaetnxtmtdhriaatnhtnsaanitccetapricvaitnatihvtReawtaceamaycsaorpsesapgcsaueesll-eal8s-t.8e(.FdSFaubaspysrprCelece5cem,epwpettoenortiraneervxxyeppsFrrteieiggssusasiitrooeednnSw1Aas)
We have revealed that C5-induced apoptosis of cancer cells occurs via extrinsic pathways and regulates the formation of the DISC complex
Summary
Apoptosis is the process of programmed cell death, generally known as morphological and biological modifications, including cell shrinkage, nuclear fragmentation, and membrane blebbing [1,2]. There are two distinct mechanisms of apoptosis: intrinsic and extrinsic pathways [3]. Stress such as radiation, hypoxia, viral infection, and increased concentration of intracellular calcium activate the intrinsic pathway [4,5]. Hypoxia, viral infection, and increased concentration of intracellular calcium activate the intrinsic pathway [4,5] This pathway is mediated by Bcl-2 (B-cell lymphoma 2) family proteins, including pro-apoptotic proteins (such as Bax, Bak, Bad, and Bid) and anti-apoptotic proteins (such asInBt.cJ.l-M2o,l.BSccil.-2X02L0,, 2a1n, 1d29M8 cl-1) [6]. Increased expression of Bax/Bak proteins is caused by cy2toocfh1r2ome c secretion and released cytochrome c interacts with apaf-1, forming a protein complex known as apaospBtcol-s2o,mBcel-vXiLa, apnrod-Mcacslp-1a)s[e6-]9. TThhee reexcterpintsoirc apnadthlwigaaynids baicntidviantegdacbtyivate cabsipnadsinegporof tdeeiantshtrhercoeuptgohr ainntdradceealtlhullaigradnodmasaiTnNs,FsRu(cthumasorthneecTrNosFisrfeaccetoprtorer-caespstoorc)iaatneddFdaesa(tChDd9o5m) ain (TaRnAdDthDe)iraTnNdFFaasn-dasFsaoscLia(tFeads dliegaatnhdd) olimgaanidns(,FrAesDpDec)t.ivInelyth[e10F,a1s1]p. aTthhewraeyc,epthtoerFaansdrelicgeapntdorbainnddinliggand biancdtiivnagtecacausspeaasefoprrmotaetiniosnthorfoduegahthin-itnradcuelcliunlagrsdigonmaaliinnsg, csoumchpalsexth(eDTISNCF),rienceclputodri-nagssFoAciDatDed, cdaesapthase-8, anddomcaasipna(sTeR-1A0D[D12) ]a.nTdhFeaFsA-aDssDoc-ilaitkeedindteeartlheudkomina-1inβ–(FcAonDvDe)r.tiInngtheenzFyasmpea(thFwLIaCyE, t)h-ienhFaibsitroecreypptorrotein w(cpac-iFtanrhsLodptFIelPaAiisg)neDai-s(n8Dcd,a-Fan[b1nLia3dInPn]d.c)taiiTni-ssahgppaeaconrsaeepuaf-tos1noer0tteiai[-,c1afD2proe]orI.gSmpTCuthaolteaatiitocFcotnAirrv,oeDaigftDtudeinl-esalahitcktoiahebrs-,iipitnnisattdesbiuerniln-che8idiun,bikgwintinssghi-gbib1cniβehnat–dwlicisionnetnggehvncebeoceramtatpiwsnpopgelpeaetexsnone(szc-Di8aysIsmSaipnCneaid)st(,ieFaFi-Lnt8AoIcCalDrunEpDdd)ri-onibFntgyAehiFDiinbnA,DittDetohrbDraryyoc, tuigonh prion-tcearascptaiosne-8wcitlheaFvAagDeDan[1d3]p. rTohmeoretefosraep, oDpIStoCsiascetixveactuestiocansp[1a4s]e.-8, which is the apoptosis initiator proCte5in(,3tβh-rAoucgethypl-rnoo-rc-aesrpyatsher-o8pchlelaamvaigdee)anisdopnreoomfothteesmapoonpotocsaissseaxineceudtiiotenrp[1e4n]o. id amides derived from ErythroCp5hl(e3uβm-Afcoertdyili-,nwohr-iecrhythharsopnhulmameridoeu)sips hoanremoafctohleogmicoanloeffcaescstasininecdluitdeirnpgenaonigdioagmeindeessisdeornivheudman umfrobmilicEarlyvtharsocpuhllaeurmenfdorodtihi,ewliahlicchellhsa(sHnUumVEerCosu)sapnhdaarmpoapcotolosgisi-cianldeuffceicntgs iancctliuvditiyngagaanignisotgceenretasiisnocnancer cehllulminaens [u1m5–b1i7li]c.aHl voawsecuvlearr, tehnedboitohleolgiaicl acleflulsnc(tHioUnVsEoCf sth) eainr dunadpeorplytoinsigs-minodluecciunlgaramcteivcihtyanaisgmaisnsotf the ancteir-ttauimn ocarnaccetrivcietyll rleinmesai[n15u–n1c7l]e.aHr.oTwheevreerf,otrhee, tbhieoloobgjieccatlivfuenocftitohnesporfestheneitrsutunddyeralyiminegdmtoldeceutelarrmine thme eecffheacntiosmf Cs 5ofotnheapaonptit-otusmisoinr aactvivaritiyetryemofatiynpuenscolefacra. nTcheerrecfeolrlse., the objective of the present study aimed to determine the effect of C5 on apoptosis in a variety of types of cancer cells
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