ESTRADIOL CONTROL OF ORNITHINE DECARBOXYLASE MESSENGER-RNA, ENZYME-ACTIVITY, AND POLYAMINE LEVELS IN MCF-7 BREAST-CANCER CELLS - THERAPEUTIC IMPLICATIONS

被引:27
作者
THOMAS, T [1 ]
THOMAS, TJ [1 ]
机构
[1] UNIV MED & DENT NEW JERSEY,ROBERT WOOD JOHNSON MED SCH,CLIN RES CTR,PROGRAM CLIN PHARMACOL,PISCATAWAY,NJ 08854
关键词
BREAST CANCER; ORNITHINE DECARBOXYLASE; POLYAMINES; ESTRADIOL;
D O I
10.1007/BF00665680
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Previous studies have shown that natural polyamines-putrescine, spermidine, and spermine-play a key role in the mechanism of action of estrogens in breast cancer. Ornithine decarboxylase (ODC) is the first enzyme of the polyamine biosynthetic pathway. To examine estrogenic regulation of polyamine biosynthesis in breast cancer, we measured ODC mRNA, ODC activity, and polyamine levels in G(1) synchronized MCF-7 cells. ODC mRNA and activity increased four-fold over that of cells in G(1) phase between 8 to 16 h after the addition of estradiol. Polyamine levels showed a sharp increase by 8 h after the addition of estradiol and decreased by 12 h. We further examined whether synthetic homologs of putrescine or spermidine could replace natural polyamines in supporting MCF-7 cell growth. Treatment of MCF-7 cells with 1 mM difluoromethylornithine (DFMO), an inhibitor of ODC, suppressed putrescine, spermidine, and spermine levels by 74, 78, and 10%, respectively, within 48 h. Cells treated with DFMO for 48 h were supplemented with either putrescine or its homologs or spermidine or its homologs. Diaminopropane, diaminobutane (putrescine), and diaminopentane were capable of fully or partially reversing the growth inhibitory effects of DFMO, whereas diaminoethane had no significant effect. Among a series of triamines, H2N(CH2)(n)NH(CH2)(3)NH2 (where n = 2 to 8; abbreviated as APn n = 4 for spermidine, or AP4), spermidine was most effective in reversing the effects of DFMO, whereas compounds with shorter or longer methylene bridging regions were less effective. AP8 was ineffective in reversing the growth inhibitory effects of DFMO. At 10 mu M concentration, AP8 also inhibited DNA synthesis by 66%, as measured by [H-3]-thymidine incorporation. These data show that MCF-7 cells have a strong requirement for polyamines for their growth and that estradiol stimulates the polyamine cascade by inducing the ODC mRNA level. Our results also suggest that polyamine homologs such as AP8 might be potentially useful in breast cancer therapy.
引用
收藏
页码:189 / 201
页数:13
相关论文
共 63 条
[1]   CELL TYPE-SPECIFIC MECHANISMS OF REGULATING EXPRESSION OF THE ORNITHINE DECARBOXYLASE GENE AFTER GROWTH-STIMULATION [J].
ABRAHAMSEN, MS ;
MORRIS, DR .
MOLECULAR AND CELLULAR BIOLOGY, 1990, 10 (10) :5525-5528
[2]  
ALLEGRA JC, 1979, CANCER RES, V39, P1973
[3]   EFFECT OF N-1,N-14-BIS-(ETHYL)-HOMOSPERMINE (BE-4-4-4) ON THE GROWTH OF U-251 MG AND SF-188 HUMAN BRAIN-TUMOR CELLS [J].
BASU, HS ;
PELLARIN, M ;
FEUERSTEIN, BG ;
DEEN, DF ;
MARTON, LJ .
INTERNATIONAL JOURNAL OF CANCER, 1991, 48 (06) :873-878
[4]  
BASU HS, 1990, CANCER RES, V50, P3137
[5]  
Beatson G.T., 1896, LANCET, V15, P153, DOI DOI 10.1016/S0140-6736(01)72307-0
[6]  
BERNACKI RJ, 1992, CANCER RES, V52, P2424
[7]   PHENOL RED IN TISSUE-CULTURE MEDIA IS A WEAK ESTROGEN - IMPLICATIONS CONCERNING THE STUDY OF ESTROGEN-RESPONSIVE CELLS IN CULTURE [J].
BERTHOIS, Y ;
KATZENELLENBOGEN, JA ;
KATZENELLENBOGEN, BS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (08) :2496-2500
[8]   AROMATASE AND ITS INHIBITORS - AN OVERVIEW [J].
BRODIE, A .
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY, 1991, 40 (1-3) :255-261
[10]   POLYAMINES IN RELATION TO HUMAN-BREAST, RECTAL AND SQUAMOUS-CELL CARCINOMA [J].
CHANDA, R ;
GANGULY, AK .
CANCER LETTERS, 1988, 39 (03) :311-318