Carcinogenesis, Vol. 22, No. 11, 1809-1817,
November 2001
© 2001 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
Cytostatic effects of 3,3'-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-
expression
Department of Nutritional Sciences and Toxicology and
1 Department of Molecular and Cell Biology, University of California-Berkeley, Berkeley, CA 94720, USA
3,3'-Diindolylmethane (DIM), a major in vivo product of indole-3-carbinol (I3C), is a promising anticancer agent derived from vegetables of the Brassica genus including broccoli, Brussels sprouts and cabbage. We report here that DIM has a potent cytostatic effect in cultured human Ishikawa endometrial cancer cells. A combination of northern blot and quantitative PCR analyses revealed that DIM induced the level of TGF-
transcripts by ~4-fold within 24 h of indole treatment. DIM also induced a 4-fold increase in the activity of the estrogen response marker, alkaline phosphatase (AP). Co-treatment of cells with the estrogen receptor (ER) antagonist ICI, or with the inhibitor of PKA-mediated activation of the ER, H89, ablated the DIM induction of both TGF- expression and AP activity. Furthermore, DIM increased the maximum stimulatory effect of estrogen on TGF- expression. Co-treatment with the protein synthesis inhibitor, cycloheximide, abolished the inductive effects of DIM, indicating differences in the mechanistic requirements of DIM and estrogen. DIM treatment also stimulated levels of secreted TGF- protein by >10-fold. The ectopic addition of TGF- inhibited the growth of Ishikawa cells, whereas incubation with a TGF- antibody partially reversed the growth inhibitory effects of DIM. Taken together, these results extend our previous findings of the ligand independent estrogen receptor agonist activity of DIM, and uncover an essential role for the stimulation in TGF- expression and the TGF- activated signal transduction pathway in the potent cytostatic effects of DIM in endometrial cancer cells.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. N. Sundar, V. Kerekatte, C. N. Equinozio, V. B. Doan, L. F. Bjeldanes, and G. L. Firestone Indole-3-Carbinol Selectively Uncouples Expression and Activity of Estrogen Receptor Subtypes in Human Breast Cancer Cells Mol. Endocrinol., December 1, 2006; 20(12): 3070 - 3082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Savino III, J. F. Evans, D. Rabinowitz, K. J. Auborn, and T. H. Carter Multiple, disparate roles for calcium signaling in apoptosis of human prostate and cervical cancer cells exposed to diindolylmethane. Mol. Cancer Ther., March 1, 2006; 5(3): 556 - 563. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chang, J. C. Tou, C. Hong, H.-A. Kim, J. E. Riby, G. L. Firestone, and L. F. Bjeldanes 3,3'-Diindolylmethane inhibits angiogenesis and the growth of transplantable human breast carcinoma in athymic mice Carcinogenesis, April 1, 2005; 26(4): 771 - 778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Anderton, M. M. Manson, R. D. Verschoyle, A. Gescher, J. H. Lamb, P. B. Farmer, W. P. Steward, and M. L. Williams Pharmacokinetics and Tissue Disposition of Indole-3-carbinol and Its Acid Condensation Products after Oral Administration to Mice Clin. Cancer Res., August 1, 2004; 10(15): 5233 - 5241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Anderton, M. M. Manson, R. Verschoyle, A. Gescher, W. P. Steward, M. L. Williams, and D. E. Mager PHYSIOLOGICAL MODELING OF FORMULATED AND CRYSTALLINE 3,3'-DIINDOLYLMETHANE PHARMACOKINETICS FOLLOWING ORAL ADMINISTRATION IN MICE Drug Metab. Dispos., June 1, 2004; 32(6): 632 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Leong, J. E. Riby, G. L. Firestone, and L. F. Bjeldanes Potent Ligand-Independent Estrogen Receptor Activation by 3,3'-Diindolylmethane Is Mediated by Cross Talk between the Protein Kinase A and Mitogen-Activated Protein Kinase Signaling Pathways Mol. Endocrinol., February 1, 2004; 18(2): 291 - 302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. H. Fowke, F.-L. Chung, F. Jin, D. Qi, Q. Cai, C. Conaway, J.-R. Cheng, X.-O. Shu, Y.-T. Gao, and W. Zheng Urinary Isothiocyanate Levels, Brassica, and Human Breast Cancer Cancer Res., July 15, 2003; 63(14): 3980 - 3986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Leibelt, O. R. Hedstrom, K. A. Fischer, C. B. Pereira, and D. E. Williams Evaluation of Chronic Dietary Exposure to Indole-3-Carbinol and Absorption-Enhanced 3,3'-Diindolylmethane in Sprague-Dawley Rats Toxicol. Sci., July 1, 2003; 74(1): 10 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Firestone and L. F. Bjeldanes Indole-3-Carbinol and 3-3'-Diindolylmethane Antiproliferative Signaling Pathways Control Cell-Cycle Gene Transcription in Human Breast Cancer Cells by Regulating Promoter-Sp1 Transcription Factor Interactions J. Nutr., July 1, 2003; 133(7): 2448S - 2455. [Abstract] [Full Text] [PDF]
|
|