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Inhibition of Nuclear Translocation of Nuclear Factor-B Contributes to 3,3'-Diindolylmethane-Induced Apoptosis in Breast Cancer Cells

Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan

Request for reprints: Fazlul H. Sarkar, Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, 715 Hudson Webber Cancer Research Center, 110 East Warren Avenue, Detroit, MI 48201. Phone: 313-966-7279; Fax: 313-966-7558. E-mail: fsarkar{at}med.wayne.edu

Dietary indole-3-carbinol (I3C), a natural compound present in vegetables of the genus Brassica, showed clinical benefits and caused apoptosis in breast cancer cells. Our laboratory and others have shown that I3C induces apoptosis in breast cancer cells mediated by inactivation of Akt and nuclear factor-B (NF-B) pathway. 3,3'-Diindolylmethane (DIM), a major in vivo acid-catalyzed condensation product of I3C, also showed some benefit in breast cancer. However, the precise molecular mechanism(s) by which DIM induces apoptosis in breast cancer cells has not been fully elucidated. Hence, we investigated whether DIM-induced apoptosis of breast cancer cells could also be mediated by inactivation of Akt and NF-B. We found that DIM induces apoptotic processes in MCF10A derived malignant (MCF10CA1a) cell lines but not in nontumorigenic parental MCF10A cells. DIM specifically inhibits Akt kinase activity and abrogates the epidermal growth factor–induced activation of Akt in breast cancer cells, similar to those observed for I3C. We also found that DIM reduces phosphorylation of IB, an inhibitor of NF-B. Our confocal microscopy study clearly showed that DIM blocks the translocation of p65, a subunit of NF-B to the nucleus. DNA binding analysis and transfection studies with IB kinase cDNA revealed that overexpression of IB kinase mediates IB phosphorylation, which activates NF-B, and this activation was completely abrogated by DIM treatment. Taken together, these results showed for the first time that the inactivation of Akt and NF-B activity also plays important roles in DIM-induced apoptosis in breast cancer cells, which seems to be more relevant to in vivo situations.

Key Words: DIM • NF-B • Akt • breast cancer cells

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