[논문]Effects of a Selective COX-2 Inhibitor Celecoxib and Soy-Isoflavones on Molecular Markers Related to Apoptosis, and COX-2 and Mapkinase Expression in Estrogen-Fed Rats

Kim, Tae-Kyung; Park, Ock Jin

Effects of a Selective COX-2 Inhibitor Celecoxib and Soy-Isoflavones on Molecular Markers Related to Apoptosis, and COX-2 and Mapkinase Expression in Estrogen-Fed Rats 원문보기

Nutritional sciences, v.8 no.1, 2005년, pp.16 - 22

Kim, Tae-Kyung (Department of Food and Nutrition, Hannam University) , Park, Ock Jin (Department of Food and Nutrition, Hannam University)

Abstract ▼ AI-Helper

The present study examined the effects of cyclooxygenase-2 (COX-2) inhibitor celecoxib or soy-isoflavones in the presence of estrogen on apoptosis related gene expression, COX-2 and mapkinase in 48-week old female rats. Expressions of bel-2 and bax proteins, which are known to be involved in the regulation of apoptosis, were investigated in mammary glands and heart tissues. The elevated expression of bel-2 expression was observed in mammary glands of celecoxib supplemented rats as well as soy-isoflavones. The mammary glands bel-2/bax ratio was found to be higher in celecoxib or soy-isoflavones supplemented rats. However, in heart tissues, expression of bel-2 and bax was in the order of control, celecoxib and soy-isoflavones. The up-regulation of COX-2 was observed in celecoxib or soy-isoflavones in mammary glands. 'The similar trend was not displayed with the mapkinase expression. In heart tissues, the down-regulation of COX-2 as well as mapkinase was observed in celecoxib or soy-isoflavones supplemented rats. Soy-isoflavones and celecoxib both had a similar regulatory pattern of bel-2, bax and COX-2 in mammary glands, and in heart tissues, only COX-2 exhibited a similar down-regulatory properly. These findings revealed that in estrogen sufficient state, celecoxib and soy-isoflavones might not exhibit proapoptotic potential or COX-2 inhibition in normal mammary glands.

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가설 설정

37) However, at the higher concentrations, both bcl-2 and bax were up-regulated. Considering that estrogens are potent mitogens in the mammary gland playing a pivotal role in the development and progression of mammary carcinoma, 38) the supplementation of estrogen with soy-isoflavones at the premenopausal state may have more detrimental effect. Tissue differences in the regulation of bcl-2 and bax were clearly shown in this study.

제안 방법

Rats were treated with estradiol, ccelecoxib + estradiol and soy-isoflavones +estradiol for four weeks. Heart tissues were collected and lysates were prepared, subjected to electrophoresis on 7% SDS-PAGE, Western- blotted, and visualized with ECL detection kit described in Materials and Methods. Lane 1.
In this study, the effects of celecoxib and soy-isoflavones on cell-signaling protein expression related to apoptosis such as bcl-2 and bax, and COX-2 and mapkinase were examined in comparison with the estrogen supplemented control. The rats used in this study were 48-week old representing the perimenopausal state, and estrogen was supplemented in the control group as well as celecoxib and estrogen groups in order to mimic the state of hormonal replacement therapy.
Rats were housed individually in an environmentallycontrolled animal laboratory with a 12-h light:dark cycle. The experimental groups were estrogen control (control), celecoxib+estrogen, and soy-isoflavones+estrogen, and three groups of rats were fed one of the three dietary regimens (Table 1) for four weeks. During this period, rats were fed the diets and water ad libitum.
The purpose of this study was to examine the modulation of the expression of bcl-2 and box, whose gene products are known to be involved in the regulation of apoptosis, by soy-isoflavones in comparison with celecoxib, a selective COX-2 inhibitor in normal estro-gen-fed female rats. Also, the interaction between apoptosis-related protein expression and COX-2 expression was examined in mammary glands and heart tissues in order to evaluate tissue differences.
To investigate the effect of celecoxib and soy-iso-flavones in the presence of estrogen on the expressions of molecular markers related to apoptosis in animal model system, bcl-2 and bax expression, and the ratio of bcl-2 and bax were monitored. In the system of estrogen supplemented rat mammary glands, celecoxib or soy-iso-flavone돕 induced the up-regulation of bcl-2 and the down-regulation of bax protein (Fig.

성능/효과

1) Each group of nine rats were fed orally high fat - high cholesterol diet containing indicating amount of either 17p~estradiol celecoxib+17p-estradiol or soy-isoflavones+ 17p-estradiol per kg diet.
The down-regulation of bcl-2 by estrogen could be reversed by the co-treatment with celecoxib or soy-isoflavones. In this study, bcl-2 lowering or bax-elevating effect of soy-isoflavones was not observed, and the highest bcl-2/bax ratio was found in soy-isoflavones supplemented rats. This observation can be explained by the differences in normal or cancerous mammary cells as well as the relatively young age of rats used.
2). It was tested whether the regulation of bcl-2 or bax was accompanied with the COX-2 modulation, and it was shown that celecoxib or soy-isoflavones treatment induced the COX-2 expression (Fig. 3). One of the mapkinases pERK was not stimulated by the up-regulation of COX-2.
This study has shown that both bcl-2 and bax were regulated by soy-isoflavones or celecoxib in mammary glands of normal female rats on the co-treatment with estrogen. In this normal tissue, the proapoptotic potential of soy-isoflavones in the presence of estrogen was not evident from the pattern of bcl-2 and bax expressions.

후속연구

The stimulation of both bcl-2 and bax was observed in the soy-isoflavones treatment. The observation of the differed response of bcl-2 and bax by mammary glands and heart requires further investigation to give full explanation.

참고문헌 (47)

Brzozowski AM, Pike CW, Pauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene GL, Gustafsson J, Carlquist M. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature 389:753-758, 1997

상세보기
Adlercreutz H, Honjo H, Higashi A, Fotsis T, Hamalainen E, Hasegawa T, Okada H. Urinary excretion of lignins and isoflavonoid phytoestrogens in Japanese men and women consuming a traditional diet. Am J Clin Nutr 54:1093-1100,1991

상세보기
Lee H P, Gourley L, Duffy SW, Esteve J, Lee J, Day NE. Dietary effects on breast cancer risk in Singapore. Lancet 336: 1197-1200, 1991
Ziegler RG, Hoover RN, Pike MC. Migration patterns and breast cancer risk in Asian-American women. J Nat Cancer Inst 85:1819-1827, 1993

상세보기
Ingram D, Sanders K, Kolybaba M, Lopez D. Case-control study of phyto-oestrogens and breast cancer. Lancet 350:990-994,1997

상세보기
Zheng W, Dai Q, Custer L, Shu XO, Wen WQ, Jin F, Franke AA. Urinary excretion of isoflavonoids and the risk of breast cancer. Cancer Epidemiol Biomark Prev 8:35-40, 1999

상세보기
Kroemer G. The proto-oncogene BcI-2 and its role in regulation apoptosis. Nature Med 3:614-620, 1997

상세보기
Reed JC BcI-2:Prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 9:451-474, 1995

상세보기
Xu ZW, Friess H, buchler MW, Solioz M. Overexpression of Bax sensitizes human pancreatic cancer cells to apoptosis induced by chemotherapeutic agents. Cancer Chemother Pharmacol 49:504-510, 2002

상세보기
Li Y, Upadhyay S, Bhuiyan M, Sarkar FH. Induction of apoptosis in breast cancer cells MDA-MB-231 by genistein. Oncogene 18:3166-3172, 1999

상세보기
Cao Y, Prescott SM. Many actions of Cyclooxygenase-2 in cellular dynamics and in cancer. J Cell Physiol 190:279-286, 2002

상세보기
Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer and development. Oncogene 18:7908-7916, 1999

상세보기
Trifan OC, Hla T. Cyclooxygenase-2 modulates cellular growth and promotes tumorigenesis. J Cell Mol Med 7:207-222, 2003

상세보기
Kismet K, Akay MT, Abbasoglu O, Ercan A. Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention. Cancer Detect Prev 28:127-142, 2004

상세보기
Ding H, Han C, Zhu J, Chen CS, D'Ambrosio SM. Celecoxib derivatives induce apoptosis via the disruption of mitochondrial membrane potential and activation of caspase 9. Int J Cancer 113:803-810, 2005

상세보기
Harvell DM, Strecker TE, Tochacek M, Xie B, Pennington KL, McComb RD, Roy SK, Shull JD. Rat strain-specific actions of $17{\beta}$ -estradiol in the mammary gland: correlation between estrogen-induced lobuloalveolar hyperplasia and susceptibility to estrogen-induced mammary cancers. Proc Natl Acad Sci, 97:2779-2784, 2000
Liehr JG, Fang WF, Sirbasku DA, Ari-Ulubelen A. Carcinogenicity of catechol estrogens in Syrian hamsters. J Steriod Biochem 24:353-356, 1986

상세보기
Li JJ, Li SA. Estrogen carcinogenesis in hamster tissues: role of metabolism. Fed Proc 46:1858-1863, 1987
Kohli E, Zalrid M, Rogan E, Cavalieri EL. Greater reactivity of estradiol-3,4-quinone versus estradiol-2,3-quinone with DNA in the formation of depurinating adducts. Proc Am Assoc Cancer Res 44:180, 2003
Toniolo PG, Levitz M, Zeleniuch-Jacquotte A, Banerjee S, Koenig KL, Shore RE, Strax P, Pasternack BS. A prospective study of endogeous estrogens and breast cancer in postmenopausal women. J Natl Cancer Inst 67:190-197, 1995
Thomas HV, Key TJ, Allen DS, Moore JW, Dowsett M, Fentiman IS, Wang DY. A prospective study of endogenous serum hormone concentrations and breast cancer risk in post-menopausal women on the island of Guernsey. Br J Cancer 76:401-405, 1997

상세보기
The Endogenous Hormones and Breast Cancer Collaborative Group. Endogenous sex hormones and breast cancer risk in post-menopausal women: reanalysis of nine prospective studies. J Natl Cancer lnst 94:606-616,2002

상세보기
Thom DM, Gardner CD, Haskell WL. Potential health benefits of dietary phytoestrogens: A review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 83:2223-2235, 1998
Knight DC, Eden JA. A review of the clinical effects of phytoestrogens. Obstet Gynecol 87:897-904, 1996

상세보기
Adlercreutz H, Mazur W. Phyto-estrogens and western diseases. Ann Med 29:95-120, 1997

상세보기
Shutt DA, Cox I. Steroid and phytoestrogen binding to sheep uterine receptors in vitro. J Endocrinol 52:299-310, 1972

상세보기
Martin PM, Horwitz KB, Ryan DS, McGuire WL. Phytoestrogen interaction with estrogen receptors in human breast cancer cells. Endocrinol 103:1860-1867, 1978

상세보기
Wang TTY, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 17:271-275, 1996

상세보기
Allred CD, Allred KF, Ju YH, Virant SM, Helferich WG. Soy diets containing varying amounts of genistein stimulate growth of estrogen-dependent (MCF-7) tumors in a dosedependent manner. Cancer Res 61:45-50, 2001

상세보기
Barkhem T, Carlsson B, Nilsson Y, Enmark E, Fustafsson J, Nilsson S. Differential response of estrogen receptor ${\alpha}$ and estrogen receptor ${\beta}$ to partial estrogen agonists/antagonists. Mole Pharm 54:105-112, 1998
Breinholt V, Hossaini A, Svendsen G, Brouwer C, Nielsen SE. Estrogenic activity of flavonoids in mice. The importance of estrogen receptor distribution, metabolism and bioavailability. Food Chem Toxicol 38:555-564, 2000

상세보기
Kuiper GGJM, Lemmen JG, Carlsson B, Corton JC, Safe SH, Van der Saag PT, Van der Burg B, Gustafsson J. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor ${\beta}$ . Endocrinol 139:4252-4263, 1998

상세보기
Routledge EJ, White R, Parker MG, Sumpter JP. Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) ${\alpha}$ and $ER{\beta}$ . J BioI Chem 275: 35968-35993, 2000
Shao A, Alpaugh ML, Fontana JA, Barsky SH. Geinstein inhibits proliferation similarly in estrogen receptor-positive and negative human breast carcinoma cell lines characterized by p21WAF1/CIP1 induction, G2/M arrest, and apoptosis. J Cell Biochem 69:44-54, 1998

상세보기
Tshilias J, Kapusta L, Slingerland J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Ann Rev Med 50:401-423, 1999

상세보기
Constatinou AI, Kamath N, Murley JS. Genistein inactivates bcl-2, delays the G2/M phase of the cell cycle, and induces apoptosis of human breast adenocarcinoma MCF-7 cells. Eur J Cancer 34:1927-1934, 1998

상세보기
Leung LK, Wang TT. Bcl-2 is not reduced in the death of MCF-7 cells at low genistein concentration. J Nutr 130:2922-2926, 2000

상세보기
Prall OW, Rogan EM, Sutherland RL. Estrogen regulation of cell cycle progression in breast cancer cells. J Steroid Biochem Mol BioI 65:169-174, 1998

상세보기
Hla T, Ristimaki A, Appleby S, Barriocanal JG. Cyclooxygenase gene expression in inflammation and angiogenesis. Ann N Y Acad Sci 696: 197-204, 1993

상세보기
Davies P, Bailey PJ, Goldenberg MM, Ford-Hutchinson A W. The role of arachidonic acid oxygenation in pain and inflammation. Ann Rev lmmunol 2:335-357, 1984

상세보기
DuBois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, Van De Putte LB, Lipsky PE. Cyclooxygenase in biology and diesease. FASEB J 12:1063-1073, 1998

상세보기
Ge T, Hughes H, Junquero DC, Wu KK, Vanhoutte PM, Boulanger CM. Endothelium-dependent contractions are associated with both augmented expression of prostaglandin H synthase-1 and hypersensitivity to prostaglandin $H_{2}$ in the SHR aorta. Cir Res 76:1003-1010, 1993
Dyer SM, Taylor DA, Bexis S, Hime NJ, Frewin DB, Head RJ. Identification of a non-endothelial cell thromboxane-like constrictor response and its interaction with the renin-angiotensin system in the aorta of spontaneously hypertensive rats. J Vasc Res 31:5-60, 1994
Wong E, Huang J, Tagari P, Riendear D. Effects of COX-2 inhibitors on aortic prostacyclin production in cholesterol-fed rabbits. Atherosclerosis 157:393-402, 2001

상세보기
Baker CS, Hall RJ, Evans TJ. Cyclooxygenase-2 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler Thromb Vasc BioI 19:646-655, 1999

상세보기
Luscher TF, Aarhus LL, Vanhoutte PM. Indomethacin improves the impaired endothelium-dependent relaxations in small mesenteric arteries of the spontaneously hypertensive rats. Am J Hypertens 3:55-58, 1990
Ghanam K, Lavagna C, Burgaud J-L, Javellaud J, Ea-Kim L, Oudart N. Involvement of cyclooxygenase 2 in the protective effect of 17 ${\beta}$ -estradiol in hypercholesterolemic rabbit aorta. Biochem Biophy Resear Comm 275:696-703, 2000

상세보기

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