Inhibition of Invasion and Induction of Apoptosis by Curcumin in H-ras-Transformed MCF10A Human Breast Epithelial Cells

  • Kim, Mi-Sung (College of Pharmacy, Duksung Wonman′s University) ;
  • Kang, Hye-Jung (College of Pharmacy, Duksung Wonman′s University) ;
  • Moon, Aree (College of Pharmacy, Duksung Wonman′s University)
  • Published : 2001.08.01

Abstract

Curcumin, a dietary pigment in turmeric, posseses anti-carcinogenic and anti-metastatic properties. The present study was conducted to study in vitro chemopreventive effects of curcumin in transformed breast cells. Here, we show that curcumin inhibits H-ras-induced invasive phenotype in MCF10A human breast epithelial cells (H-ras MCF10A) and downregulates matrix metalloproteinase (MMP)-2 dose-dependently. Curcumin exerted cytotoxic effect on H-ras MCF10A cells in a concentration-dependent manner. Curcumin-induced cell death was mainly due to apoptosis in which a prominent downregulation of Bcl-2 and upregulation of Bax were involved. We also suggest a possible involvement of caspase-3 in curcumin-induced apoptosis. Curcumin treatment resulted in the production of reactive oxygen species (ROS) in H-ras MCF10A cells. Apoptotic event by curcumin was significantly inhibited by pretreatment of an antioxidant N-acetyl-$_L$-cysteine (NAC), suggesting redox signaling as a mechanism responsible for curcumin-induced apoptosis in H-ras MCF10A cells. Taken together, our results demonstrate that curcumin inhibits invasion and induces apoptosis, proving the chemopreventive potential of curcumin .

Keywords

References

  1. J. Cell. Biochem. v.64 Mammalian cell death protease: a family of highly conserved aspartate specific cytosine proteases Alnemri,E.S.
  2. FEBS Lett. v.499 Differential regulation of apoptosis in AK-5 tumor cells by the proto-oncogene Bcl-2: presence of Bcl-2 dependent and independent pathways Anjum,R.;Khar,A.
  3. J. Immunol. v.130 no.4 Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation Bass,D.A.;Parce,J.W.;Dechatelet,L.R.;Szejda,P.;Seeds,M.C.;Thomas,M.
  4. J. Biol. Chem. v.272 no.1 Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation Bae,Y.S.;Kang,S.W.;Seo.M.S.;Baines,I.C.;Tekle,E.;Chock,P.B.;Rhee,S.G.
  5. Proc. Natl. Acad. Sci. v.91 Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells Bernhard,E.J.;Gruber,S.B.;Muschel,R.J.
  6. FEBS Lett. v.456 Curcumin mediated apoptosis in AK-5 tumor cells involves the production of reactive oxygen intermediates Bhaumik,S.;Anjum,R.;Rangaraj,N.;Pardhasaradhi,B.V.;Khar,A.
  7. Mutat. Res. v.428 Anti-tumor promoting potential of naturally occurring diarylheptanoids structurally related to curcumin Chun,K.S.;Shon,Y.;Kim,H.S.;Kim,O.H.;Park,K.K.;Lee,J.M.;Lee,J.;Lee,J.Y.;Moon,A.;Lee,S.S.;Surh,Y.J.
  8. Soc. Neurosci. Abstr. v.22 Cholinergic neuron-specific overexpression of Bax in ChAT Bax transgenic mice Cooper,J.D.;Michaelidis,T.M.;Tzimagiorgis,G.Z.;Sendtner,M.;Meyer,M.;Thoenen,H.
  9. Prostate v.47 Therapeutic potential of curcumin in human prostate cancer.III. Curcumin inhibits proliferation, induces apoptosis, and inhibits angiogenesis of LNCaP prostate cancer cells in vivo Dorai,T.;Cao,Y.C.;Dorai,B.;Buttyan,R.;Katz,A.E.
  10. Mut. Res. v.307 Antimutagens as cancer chemopreventive agents in the diet Ferguson,L.R.
  11. Biochem. Biophys. Res. Commun. v.246 Zinc suppresses apoptosis of U937 cells induced by hydrogen peroxide through an increase of the Bcl-2/Bax ratio Fukamachi,Y.;Karasaki,Y.;Sugiura,T.;Itoh,H.;Abe,T.;Yamamura,K.;Higashi,K.
  12. Cancer Res. v.51 Inhibitory effects of curcumin on in vitro lipoxygenase and cyclooxygenase activities in mouse epidermis Huang,M.T.;Lysz,T.;Ferraro,T.;Abidi,T.F.;Laskin,J.D.;Conney,A.H.
  13. Biochem. Biophys. Acta. v.1224 Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reacitive oxygen species in rat peritoneal macrophages Joe,B.;Lokesh,B.R.
  14. Cancer Lett. v.165 Capsaicin induced apoptosis in SK-Hep-1 hepatocarcinoma cells involves Bcl-2 downregulation and caspase-3 activation Jung,M.Y.;Kang,H.J.;Moon,A.
  15. Eur. J. Cancer Chemopreventive allythiopyridazine derivatives induce apoptosis in SK-Hep-1 hepatocarcinoma cells through a caspase-3-dependent mechanism Jung,M.Y.;Kwon,S.K.;Moon,A.
  16. Cancer Lett. v.157 Apicidin, an inhibitor of histone deacetylase, prevents H-ras-induced invasive phenotype Kim,M.S.;Son,M.W.;Kim,W.B.;Park,Y.I.;Moon,A.
  17. J. Kor. Assoc. Cancer Prevention v.4 Curcumin inhibits invasive phenotype of H-ras transformed human breast epithelial cells and suppresses matrix metallo-proteinase-2 activity Kim,M.S.;Moon,A.
  18. J. Toxicol. Pub. Health v.14 Roles of matrix metalloproteinase-2 and -9 on the H-ras-induced invasive phenotype in human breast epithelial cells and human fibrosarcoma cells Kim,M.S.;Won,J.H.;Moon,A.
  19. Oncogene v.16 Overexpression of Bax gene sensitizes K562 erythroleukemia cells to apoptosis induced by seletive chemotherapeutic agents Kobayashi,T.;Ruan,S.;Clodi,K.;Kliche,K.O.;Shiku,H.;Andreeff,M.;Zhang,W.
  20. Arch. Pharm. Res. v.23 Signal transduction events elicited by natural products: role of MAPK and caspase pathways in homeostatic response and induction of apoptosis Kong,A.N.;Yu,R.;Chen,C.;Mandlekar,S.;Primiano,T.
  21. Oncology v.55 Curcumin inhibits SK-Hep-1 hepatocellular carcinoma cell invasion in vitro and suppresses matrix metallo-proteinse-9 secretion Lin,L.I.;Ke,Y.F.;Ko,Y.C.;Lin,J.K.
  22. Cancer Lett. v.141 Anti-metastatic activity of curcumin and catechin Menon,L.G.;Kuttan,R.;Kuttan,G.
  23. Anticancer Drugs v.8 Antiproliferative effect of curcumin (diferuloylmethane) against human breast tumor cell lines Mehta,K.;Pantazis,P.;McQueen,T.;Aggarwal,B.B.
  24. Int. J. Cancer v.85 H-ras, but not N-ras, induces an invasive phenotype in human breast epithelial cells: A role for MMP-2 in the H-ras induced invasive phenotype Moon,A.;Kim,M.S.;Kim,T.G.;Kim,S.H.;Kim,H.E.;Chen,Y.Q.;Kim,H.R.C.
  25. J. Biochem. Mol. Biol. v.29 Expression of type IV collagenase genes and ras oncogene in various human tumor cell lines Moon,A.;Park,S.H.;Lee,S.H.
  26. Nature (Lond.) v.376 Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis Nicholson,D.W.;Ali,A.;Thornberry,N.A.;Vaillancourt,J.P.;Ding,C.K.;Gallant,M.;Gareau,Y.;Griffin,P.R.;Labelle,M.;Lazebnik,Y.A.;Munday,N.A.;Raju,S.M.;Smulson,M.E.;Yamin,T.T.;Yu,V.L.;Miller,D.K.
  27. Cell v.74 Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death Oltvai,Z.N.;Milliman,C.L.;Korsmeyer,S.J.
  28. Carcino-genesis v.17 Effects of the phytochemicals, curcumin and quercetin, upon azoxymethane-induced colon cancer and 7,12-dimethylbenz[α]anthracene-induced mammary cancer in rats Pereira,M.A.;Grubbs,C.J.;Barnes,L.H.;Li,H.;Olson,G.R.;Eto,I.;Juliana,M.;Whitaker,L.M.;Kelloff,G.J.;Steele,V.E.;Lubet,R.A.
  29. Cell Death Differ. v.6 Emerging roles of caspase-3 in apoptosis Porter,A.G.;Janike,R.U.
  30. Breast Cancer Res.Treat v.54 Differential sensitivity of human mammary epithelial and breast carcinoma cell lines to curcumin Ramachandran,C.;You,W.
  31. Proc.Natl.Acad.Sci. v.49 Inhibition of carcinogenesis by minor anutrient constituents of the diet Wattenberg,L.W.
  32. Science v.275 Prevention of apoptosis by bcl-2: release of cytochrome c from mitochondria blocked Yang,J.;Liu,X.;Bhalla,K.