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J Biol Chem, Vol. 273, Issue 7, 3838-3847, February 13, 1998
From the Department of Molecular and Cell Biology and Cancer
Research Laboratory and the § Department of Nutritional
Sciences, University of California, Berkeley, California 94720
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.
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