Abstract
Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables such as cabbage, broccoli, and Brussels sprouts, has been shown to reduce the incidence of spontaneous and carcinogen-induced mammary tumors. Treatment of cultured human MCF7 breast cancer cells with I3C reversibly suppresses the incorporation of [3H]thymidine without affecting cell viability or estrogen receptor (ER) responsiveness. Flow cytometry of propidium iodide-stained cells revealed that I3C induces a G1 cell cycle arrest. Concurrent with the I3C-induced growth inhibition, Northern blot and Western blot analyses demonstrated that I3C selectively abolished the expression of cyclin-dependent kinase 6 (CDK6) in a dose- and time-dependent manner. Furthermore, I3C inhibited the endogenous retinoblastoma protein phosphorylation and CDK6 phosphorylation of retinoblastoma in vitro to the same extent. After the MCF7 cells reached their maximal growth arrest, the levels of the p21 and p27 CDK inhibitors increased by 50%. The antiestrogen tamoxifen also suppressed MCF7 cell DNA synthesis but had no effect on CDK6 expression, while a combination of I3C and tamoxifen inhibited MCF7 cell growth more stringently than either agent alone. The I3C-mediated cell cycle arrest and repression of CDK6 production were also observed in estrogen receptor-deficient MDA-MB-231 human breast cancer cells, which demonstrates that this indole can suppress the growth of mammary tumor cells independent of estrogen receptor signaling. Thus, our observations have uncovered a previously undefined antiproliferative pathway for I3C that implicates CDK6 as a target for cell cycle control in human breast cancer cells. Moreover, our results establish for the first time that CDK6 gene expression can be inhibited in response to an extracellular antiproliferative signal.
Highlights
Phenomenon is likely due to the diverse spectrum of dietary and environmental compounds that can regulate the function and proliferation of mammalian cells by influencing hormone receptor signal transduction pathways [3, 4]
I3C Reversibly Inhibits the Growth and Induces a G1 Cell Cycle Arrest of Human MCF7 Breast Cancer Cells—As an initial test to determine whether dietary indoles can directly regulate the growth of human breast cancer cells, MCF7 cells were cultured at subconfluency in medium supplemented with 10% fetal bovine serum (FBS) and 10 g/ml insulin and treated with several concentrations of I3C for 48 h
The lowest concentration of I3C that maximally inhibited the growth of MCF7 cells without affecting viability was 100 M, and this level of the indole was routinely used in subsequent experiments
Summary
Phenomenon is likely due to the diverse spectrum of dietary and environmental compounds that can regulate the function and proliferation of mammalian cells by influencing hormone receptor signal transduction pathways [3, 4] Several classes of these naturally occurring hormone-like chemicals have been implicated in the control of tumor cell growth and as chemopreventative agents. ICZ appears to mediate its antiestrogenic effects by the direct binding to the Ah receptor (aromatic hydrocarbon or dioxin receptor), inducing cytochrome P450 CYP1A1 gene expression [19], which can alter estrogen metabolism, thereby effectively decreasing the amount of circulating estrogen This reduction in circulating estrogen leads to the decreased growth of estrogen-responsive mammary tissue and, presumably, a protective effect against breast cancer. The estrogen-induced activation of CDK4 and CDK2 during progression of human breast cancer cells between the G1 and S phases is accompanied by the increased expression of cyclin D1 and decreased association of the CDK inhibitors with the cyclin
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