Journal Article

Cytostatic effects of 3,3′-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-α expression

Hoyee Leong, Gary L. Firestone and Leonard F. Bjeldanes

in Carcinogenesis

Volume 22, issue 11, pages 1809-1817
Published in print November 2001 | ISSN: 0143-3334
Published online November 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.11.1809
Cytostatic effects of 3,3′-diindolylmethane in human endometrial cancer cells result from an estrogen receptor-mediated increase in transforming growth factor-α expression

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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-α 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-α expression and AP activity. Furthermore, DIM increased the maximum stimulatory effect of estrogen on TGF-α 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-α protein by >10-fold. The ectopic addition of TGF-α inhibited the growth of Ishikawa cells, whereas incubation with a TGF-α 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-α expression and the TGF-α activated signal transduction pathway in the potent cytostatic effects of DIM in endometrial cancer cells.

Keywords: AhR, aryl hydrocarbon receptor; AP, alkaline phosphatase; CTr, cyclic trimer; DIM, 3,3′-diindolylmethane; E2, estradiol; EGFR, epidermal growth factor receptor; ER, estrogen receptor; I3C, indole-3-carbinol; TGF-α, transforming growth factor-α; ICZ, indolo[3,2-b]carbazole; JNK, c-Jun NH2 terminal kinase; MAPK, mitogen activated protein kinase.

Journal Article.  7024 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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