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DNA topoisomerase I 억제제 β-lapachone에 의한 전립선 암세포의 성장억제 기전연구

Up-regulation of Bax is associated with DNA topoisomerase I inhibitor β-lapachone-induced apoptosis in human prostate carcinoma cells

  • 공규리 (동의대학교 한의과대학 생화학교실) ;
  • 최병태 (동의대학교 해부학교실 및 한의학연구소) ;
  • 최영현 (동의대학교 한의과대학 생화학교실)
  • 발행 : 2002.08.01

초록

남미지역에 서식하는 Tabebuia avellanedae의 수피에서 동정된 천연 quinone계 물질인 $\beta$-lapachone은 DNA topoisomerase I 억제제 이외 다양한 약리학적 기능이 있을 것으로 추정되지만 그 기능이 명확하지 않다. $\beta$-lapachone의 생리활성 기전 해석의 일환으로 본 연구에서는 인체 전립선 DU-145 암세포주의 성장에 미치는 $\beta$-lapachone의 영향을 조사하였다. p-lapachone이 함유된 배지에서 자란 암세포들은 $\beta$-lapachone 처리 농도 의존적으로 성장이 억제되었으며, 이는 apoptosis가 유발된 세포에서 특징적으로 관찰되는 chromatin condensation 및 DNA fragmentation 현상을 유발하였고, DNA flow cytometry 분석결과 apoptotic-sub Gl기에 해당하는 세포들의 빈도도 증가되었다. 또한 poly (ADP-ribose) polymerase 및 $\beta$-catenin 단백질의 발현에서도 apoptosis 유발 특이적인 분해 현상을 보여주었으며, DU-145 전립선 암세포에서 $\beta$-lapachone에 의한 이러한 apoptosis의 유발에는 Bax의 발현증가에 따른 Bcl-2 발현의 감소가 중요한 역할을 할 고 있는 것으로 사료된다.

The DNA topoismerase I inhibitor $\beta$-lapachone, the product of a tree from South America, is known to exhibit various biological properties, however the mechanisms of which are poorly understood. In the present report, we investigated the effects of $\beta$-lapachone on the growth of human prostate carcinoma DU-145 cells. Upon treatment with $\beta$-lapachone, a concentration-dependent inhibition of cell viability was observed and cells developed many of the hallmark features of apoptosis, including condensation of chromatin and DNA fragmentation. Flow cytometry analysis confirmed that $\beta$-lapachone increased populations of apoptotic-sub Gl phase. In addition, proteolytic cleavages of poly (ADP-ribose) polymerase (PARP) and $\beta$-catenin protein were observed after treatment of $\beta$-lapachone. These apoptotic effects of $\beta$-lapachone in DU-145 cells were associated with marked induction of Bax protein, however the levels of Bcl-2 expression were decreased in a dose-dependent manner.

키워드

참고문헌

  1. Exp.Cell.Res. v.256 The Bcl-e protein family Antonsson,B.;J.C.Martinou https://doi.org/10.1006/excr.2000.4839
  2. Am.J.Pathol v.136 Apoptosis.The role of the endonuclease Arends,M.J.;R.G.Morris;A.H.Wylli
  3. Pharmacol.Res. v.29 Cell survical and death programmes Chiarugi,V.;L.Magnelli;A.Turchetti;M.Cinelli;S.Cavari;M.Ruggiero https://doi.org/10.1016/1043-6618(94)80034-0
  4. Int.J.Oncol. v.18 Apoptotic activity of novel bile acid derivatives in human leukemic T cells through the activation of caspases Choi,Y.H.;E.O.Im;H.S.Suh;Y.E.Jin;W.H.Lee;Y.H.Yoo;K.W.Kim;N.D.Kim
  5. Int.J.Oncol. v.17 Induction of apotosis by ursolic acid through activation of caspases and down-regulation of c-IAPs in human prostate epithelial cells Choi,Y.H.;J.H.Baek;M.A.Yoo;H.Y.Chung;N.D.Kim;K.W.Kim
  6. Int.J.Oncol. v.21 Phosphorylation of p53, induction of Bax and activation of caspases during β-lapachoine- mediated apoptosis in human prostate epithelial cells Choi,Y.H.; M.J. Kim;S.Y.Lee;Y.N.Lee;G.Y.Chi;H.S.Eom;N.D.Kim;B.T.Choi
  7. J.Biol.Chem. v.272 Regulation of cyclin D1 by calpain prostease Choi,Y.H.;S.J.Lee;P.Nguyen;J.S.Jang;J.Lee;M.L.Wu;E.Takano;M.Maki;P.A.Henkart;J.B.Trepel https://doi.org/10.1074/jbc.272.45.28479
  8. Jpn.J.Cancer Res. v.91 p53-independent induction of p21(WAF1/CIP1),reduction of cyclin in human prostate carcinoma cells Choi,Y.H.;W.H.Lee;K.Y.Park;L.Zhang https://doi.org/10.1111/j.1349-7006.2000.tb00928.x
  9. Annu.Rev.Immunol v.10 Apoptosis and programmed cell death immunity Cohen,J.J.;R.C.Duke;V.A.Fadok;K.S.Sellins https://doi.org/10.1146/annurev.iy.10.040192.001411
  10. Biochem.Pharmacol. v.28 β-lapachone enhancement of lipid peroxidation and superoxide anion and gydrogen peroxide formation by sarcoma 180 ascites tumor cells Dacampo.R.;F.S.Cruz;A.Boveris;R.P.Muniz;D.M.Esquivel https://doi.org/10.1016/0006-2952(79)90348-4
  11. Mol.Pharmacol. v.59 Induction of CDK inhibitors (p21(WAF1)) and Bak in the β-lapachone-induced apoptosis of human prostate cancer cells Don,M.J.;Y.H.Chang;K.K.Chen;L.K.Ho;Y.P.Chau
  12. Cell.Biol.Int. v.17 Multople pathways ro apoptosis Evans,V.G https://doi.org/10.1006/cbir.1993.1087
  13. Int. J.Biochem.Cell.Biol v.31 Apoptosis-associated cleavade of β-catenin in human colon cancer and rat hepatoma cells Fukuda.K https://doi.org/10.1016/S1357-2725(98)00119-8
  14. Arch.Biochem.Biophys v.240 Effects of β-lapachone, a peroxide-generation quinone, on macrolecue synthesis and degration in Try-panosoma cruzi Goijman,S.G.;A.O.Stoppani https://doi.org/10.1016/0003-9861(85)90033-5
  15. Planta Med. v.60 Comparison of antibacterial and antifungal activities of lapachol and β-lapachone Guiraud,P.;R.Steiman,G.M.Campos-Takati;F.Seigle-Murandi;M.Simeon de buocherg https://doi.org/10.1055/s-2006-959504
  16. Physiol.Rev. v.80 Tissue-specifiec Bcl-2 protein partners in apoptosis:An ovarian paradigm Hsu.S.Y.;A.J.Hsueh
  17. Mol.Med. v.5 β-lapachone induces cell cycle arrest and apoptosis in human colon cancer cells Huang.L;A.B.Pardee
  18. Exp.Eye.Res. v.67 The topoisomerase I inhibitors,camptothecin and β-lapachone, induce apoptosis of human retinal pigment epithelial cells Hueber,A.;P.Esser,K.Heimann;N.Kociok;S.Winter;M.Weller https://doi.org/10.1006/exer.1998.0544
  19. Cancer Metastasis.Res. v.18 Cell adhesion molecules in the development and progression of malignant melanoma Johnson,J.P. https://doi.org/10.1023/A:1006304806799
  20. Cancer.Res. v.53 Specific proteolytic cleavage of poly(ADP-ribose) polymerase:an early marker of chemotherapy-induced apoptosis Kaufmann,S.H.;S.Desnoyers;Y.Ottaviano;N.E.Davidson;G.G.Poirier
  21. Histol.Histopathol v.13 β-lapachone induced cell death in human hepatoma(HepA2)cells Lai.C.C.;T.J.Liu;L.K.Ho;M.J.Don;Y.P.Chau
  22. Nature v.371 Cleavage of poly ADP-ribose polymerase by a proteinase with properties like ICE. Lazebnik,Y.A.;S.H.Kaufmann;S,Desnoyers;G.G.Poirier;W.C.Earnshaw https://doi.org/10.1038/371346a0
  23. Acta.Biochem.Pol. v.46 Mitochondria, Oxidative stress, and antioxidant defences Lenaz,G.;C.Bovina;G.Formiggini;G.P.Gastelli
  24. Cancer.Res. v.55 Induction of apoptosis by β-lapachone in human prostate canver cells Li,C.J.;L.Wang;A.B.Pardee
  25. J.Biol.Chem. v.268 β-Lapachone, a novel DNA topoisomerase I inhibitor with a mode of action different from camptothecin Li,C.J.;L.Averboukh;A.B.Pardee
  26. Ann.Trop.Med.Parasitol v.72 In vitro and in vivo evaluation of the toxicity of 1,4-napthoquinone and 1,2--naphthoquinone derivatives against Trypansoma cruzi Lopez,J.N.;F.S.Cruz;R.Docampo.;M.E.Vascpmcellos;M.C.Sampaio;A.V.Pinto;B.Gilbert
  27. Nature v.362 p53 is required for radiation -induced apoptosis in mouse thymocytes Lowe,S.W.;E.M.Schmitt;S.W.Smith;B.A.Osborme;T.Jacks https://doi.org/10.1038/362847a0
  28. J.Biol.Chem. v.271 Phosphatiedylserine externaliztion during CD95-induced apopotsis of cells and cytoplasts ICE/CED-3 protease activity Martin,S.J.;D.M.Finucane;G.P.Amarante-Mendes;G.A.O'Brien;D.R.Green https://doi.org/10.1074/jbc.271.46.28753
  29. Cell v.88 Apoptosis by death factor Nagata,S https://doi.org/10.1016/S0092-8674(00)81874-7
  30. Exp.Cell.Res. v.255 Activation of a cysteine protease in MCF-7 and T47D brest cancer cells during β-lapachone-mediated apoptosis Pink,J.J.;S.Wuerzberger-Davis;C.Tagliarino;S.M.Planchon;X.Yang;C.J.Froelich:D.A.Boothman https://doi.org/10.1006/excr.1999.4790
  31. Cancer.Res. v.55 β-lapachone-mediated apoptosis in human promyelocytic leukemia (HL-60) and human prostate canver cells:a p53-independent response Planchom,S.M.;S.Wuerzberger;B.Frydman;D.T.Witiak;P.Hutson;D.R.Church;G.Wilding;D.A.Boothman
  32. Oncol.Rep. v.6 Bcl-2 protects against β-lapachone-mediated caspase 3 activation and apoptosis in gyman myeloid leukemia(HL-60) cells Planchom,S.M.;S.Wuerzberger-Davis; J.J.Pink;K.A. Robertson;W.G.Robertson;D.A.Boothman
  33. Nature v.391 Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Rosse,T.;R.Olivier;L.Monney;M.Rager;S.Conus;I.Fellay;B.Jansen;C.Broner https://doi.org/10.1038/35160
  34. Rev.Reprod v.5 Cadherins;crucial regulators of structure and fuction on reproductive tissues Rowlands,T.M.J.M.Symonds,R.Farookhi;O.W.Blaschuk https://doi.org/10.1530/ror.0.0050053
  35. J.Med.Chem. v.27 β-lapachone :synthesis of derivatives and activities in tumor models Schaffner-Sabba,K.;K.H.Schmidt-Ruppin;W.Wehrli;A.R.Schuerch;J.W.Wasley https://doi.org/10.1021/jm00374a010
  36. Science v.263 Permature p34cdc2 activation required for apoptosis Shi,L.;W.K.Nishioka,J.Th'ng;E.M.Bardury;D.W.Litchfield;A.H.Greenberg https://doi.org/10.1126/science.8108732
  37. Cancer.Res. v.59 Activation of c-Jin NH2-terminal kinase and subsequent CPP32/Yama during topoisomerase inhiitor β-lapachone -induced apoptosis through an oxidation -dependent pathway Shiah.S.G.;S.E.Chuang;Y.P.Chau.S.C.Shen;M.L.Kuo
  38. J.Biol.Chem. v.275 Apoptosis-induced cleavage of β-catenin by caspase-3 results in proteolytic fragments with reduced tran-sacrivation potentail Steinhusen,U.;V.Badock;A.Bauer;J.Behrens;B.Wittman-Liebold;B.Dorken;K.Bommnet https://doi.org/10.1074/jbc.M001458200
  39. Oncogene v.9 Induction of p21(WAF-1/CIPI) during differentiation Steinman,R.A.;B.Hoffman;A.Iro;C.Guilouf;D.A.Lievermann;M.E.E1-Houseini
  40. Cell v.81 Yama/CPP32, a mammalian homolog of CED-3,is a CrmA-inhibitable protease that cleaver the death suvstrate poly(ADP-ribose) polymerase Tewari.M.;L.T.Quan;K.O'Rourke;S.Desnoyers,Z.Zeng;D.R.Beidler;G.G.Poirier;G.S.Salvesen;V.M.Dixit https://doi.org/10.1016/0092-8674(95)90541-3
  41. Int.J.Cancer v.73 Topoisomerase-I inhibitors for human malignant glioma:differential modulation of p53,P21 bax and bcl-2 experssion and of CD95-mediated apoptosis by camptothecin and β-lapachone Weller,M.;S.Winter;C.Schmidt;P.Esser;A.Fontana;J.Dichgans;P.Groscurth https://doi.org/10.1002/(SICI)1097-0215(19971127)73:5<707::AID-IJC16>3.0.CO;2-2
  42. Br.J.Surg v.87 E-cadherin-catenin cell-cell adhesion complex and human cancer Wijnhoven,B.P;W.N.Dinjens;M.Pignatelli https://doi.org/10.1046/j.1365-2168.2000.01513.x
  43. Cancer.Res. v.58 Induction of apoptosis in MCF-7:WS8 breast cancer cells by β-lapachone Wuerzberger,S.M.;J.J.Pink;S.M.Planchon;K.L.Byers;W.G.Bornmannn;D.A.Boothman
  44. Oncogene v.9 Induction of bax by genotoxic stress in human cells correlates with normal p53 status and apoptosis Zhan,Q.;S.Fan;I.Bae;C.Guillouf;D.A.Liebermann;P.M.O'Connor;A.J.Jr.Fornace