Abstract
Cyprodinil (CYP) is a pyrimidine amine fungicide that has been extensively used in agricultural areas. 3,3′-Diindolylmethane (DIM) is a derivative of the dietary phytoestrogen, indole-3-carbinol (I3C), which is derived from cruciferous vegetables and considered to be a cancer-preventive phytonutrient agent. In this study, the effects of CYP and DIM were examined on the cell viability, invasion, and metastasis of human endometrial cancer cells, Ishikawa, via epithelial mesenchymal transition (EMT). CYP increased the level of cell viability of Ishikawa cells compared to DMSO as a control, as did E2. Ishikawa cells lost cell-to-cell contact and obtained a spindle-shaped or fibroblast-like morphology in response to the application of E2 or CYP by the cell morphology assay. In the cell migration and invasion assay, CYP enhanced the ability of migration and invasion of Ishikawa cells, as did E2. E2 and CYP increased the expressions of N-cadherin and Snail proteins, while decreasing the expression of E-cadherin protein as EMT-related markers. In addition, E2 and CYP increased the protein expressions of cathepsin D and MMP-9, metastasis-related markers. Conversely, CYP-induced EMT, cell migration, and invasion were reversed by fulvestrant (ICI 182,780) as an estrogen receptor (ER) antagonist, indicating that CYP exerts estrogenic activity by mediating these processes via an ER-dependent pathway. Similar to ICI 182,780, DIM significantly suppressed E2 and CYP-induced proliferation, EMT, migration, and invasion of Ishikawa cancer cells. Overall, the present study revealed that DIM has an antiestrogenic chemopreventive effect to withdraw the cancer-enhancing effect of E2 and CYP, while CYP has the capacity to enhance the metastatic potential of estrogen-responsive endometrial cancer.
Highlights
Phytoestrogens of plant origin, such as plant polyphenols, are xenoestrogens that show structural similarity to 17β-estradiol (E2), the mammalian steroid hormone [1]
Genistein, a major soy isoflavone, and 3,3 -diindolylmethane (DIM), a derivative of the dietary phytochemical complex, indole-3-carbinol (I3C), which is derived from cruciferous vegetables, are phytoestrogens known for reducing the risk of prostate and breast cancer [6,7]. 3,3 -diindolylmethane has been reported to influence the prevention of estrogen-dependent cancers similar to fulvestrant (ICI 182,780), an estrogen receptor (ER) antagonist [8]
We investigated the concurrent effects of CYP as an endocrine disrupting chemicals (EDCs) and DIM as a phytoestrogen on the cell viability, migration, and invasion capacities of Ishikawa endometrial cancer cells that are estrogen responsive
Summary
Phytoestrogens of plant origin, such as plant polyphenols, are xenoestrogens that show structural similarity to 17β-estradiol (E2), the mammalian steroid hormone [1]. Swell wereCtroenavteerdsewlyi,thwEhe2n(1tr0e−a9teMd w) oitrhCaYmPix(1tu0r−e8oMf I)CfIo1r8224,7h80, t(h1e0−n8 uMm) obrerDoIMf Is(h10ik−7aMw)aacnedllsE2th(a1t0−m9 Mov) eodr from the toCpYPch(1a0m−8bMer),tothtehneubmobtteormof cihntarmudbeedr cwelalss wsiagsnriefidcuacnetdlytoauthgemceonntterodl (leFvigelu(rFeig5u).reC5oAn,vBe).rsTehleys,ewhen treated with a mixture of ICI 182,780 (10−8 M) or DIM (10−7 M) and E2 (10−9 M) or CYP (10−8 M), the number of intruded cells was reduced to the control level (Figure 5A,B). 6 of 13 6 of 136 of 13 results indicate that CYP enhanced the invasion capacity of Ishikawa cells through an CasYdPECiRdYerEC-nePERdYsh--2uePidanp,l-tenidaesnpcnnudeeddcinudneedctddnetheihdtncianeattisvtniiDesganvisngIavMitsnaoahilaonsailhnintioongaonfgsCfIptcYsIphasahPahtepithkihakcwaewcawniwapathyayayaa,c,cnocieaceatflsyelsllIdssstd.d.hoiitiddrhkeeaEsEwt22ri,,aanaivacnnanedsEdlilo2stnthtohharatrctCoaDpuDYIagMPIcMhi-tiynhahnadsaouEsfctRhetIe-dhsdehcieinakpcpvaaeaawpncsaidaitcoyeintncytetoollsftsiorIgessntrhthearirsaklotiianrnuawggiEhnap2caEaeot2nhlrlwso. ray, FmigiguFriragFmetuiiig4orgu.enrra.eE4tCi.fo4feEn.el.fcElfsCtefsfcewetlocsletsfsroweIofCetfIIrCIeC1aIt8Itr12ee18d,a872t28e,w7,d078i80two0hroiot(rhDAr DID)(MAI0IMM).1o0%.noo1nn%DEEE2MD22-M--SooOSorrOr,CC,ECYYE2YP2(P-1(i-i1n0ni0nd−d−d9u9uucMMceced)e,)dd,CIsCIIYhssYPihhkPiia(kk1w(aa01waw−08 a−eaMn8e)ed,nMno(dmdB)o,o)em(mtaBreime)atrtlaiirxacimtalunlcricxeacentaoruncfrcecEeerel2lrocefclEel l2l w(Dr41e0aI0c×Mso−((mr4w11.evr0900aec(i((r4wsT×eg1M11o−−espi0.rhg97r00a0cv×yeTano−−seM)−rM.ea97thiveorToit7fpMr)pMoeeyei)fhrece,Mrndeow)paepy)orCar.r,nceoetf)etpooCYahter,CrerswlefeutcndryrpePCYerseweenlotcedpdlnYPease(ucsdtoeip1tgnPhtftnucat(eiwf0ieterh1tvgenddma(ie−c0r1rveegeodeetee−08aelreeidfe8eyno−evslrd8MyttM,ot,feeaihitMt,fmaaaatlirtr))emyhhettrnet)weheh,eaaaeaewdedsaaeetnnntse,hwnnweodd,fwdwrddersuaeeaoosaenoIcnIrtnuIcmCnwrcrCeuaCdresandadIaniIccat0pdcttdc(arrhrcd((ad1thhae1ep1hpruar0a0tcee0(teeottp−crtA−uodcuda−8ca8fehrovror)Mede8Meeevvwweaaas0dddMeerrr)a)ce.ii,,eerryh1ttntaawyyhho)o%ttt0t,aprpreriaa0,0roateardr(rD,(reh2,eCareeCe2a14s2taa1sMa)a(4me)4,esCa,naam,naaaSm1ettatt)atnOthmneLnemmeeLnaddeteda,adi,daximLccmEmpxm4c4tahh4ut2aih88
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