Activation and potentiation of interferon-γ signaling by 3,3′-diindolylmethane in MCF-7 breast cancer cells

3,3'- Diindolylmethane ( DIM), a natural autolytic product in plants of the Brassica genus, including broccoli, cauliflower, and Brussels sprouts, exhibits promising cancer protective activities, especially against mammary neoplasia in animal models. We observed previously that DIM induced a G 1 cell-cycle arrest and strong induction of cell-cycle inhibitor p21 expression and promoter activity in both estrogen-responsive and -independent breast cancer cell lines. We showed recently that DIM up-regulates the expression of interferon gamma(IFN gamma) in human MCF-7 breast cancer cells. This novel effect may contribute to the anticancer effects of DIM because IFN gamma plays an important role in preventing the development of primary and transplanted tumors. In this study, we observed that DIM activated the IFN gamma signaling pathway in human breast cancer cells. DIM activated the expression of the IFN gamma receptor (IFNGR1) and IFN gamma-responsive genes p56- and p69-oligoadenylate synthase (OAS). In cotreatments with IFN gamma, DIM produced an additive activation of endogenous p69-OAS and of an OAS-Luc reporter and a synergistic activation of a GAS-Luc reporter. DIM synergistically augmented the IFN gamma induced phosphorylation of signal transducer and activator of transcription factor 1, further evidence of DIM activation of the IFN gamma pathway. DIM and IFN gamma produced an additive inhibition of cell proliferation and a synergistic increase in levels of major histocompatibility complex class-1 (MHC-1) expression, accompanied by increased levels of mRNAs of MHC-1-associated proteins and transporters. These results reveal novel immune activating and potentiating activities of DIM in human tumor cells that may contribute to the established effectiveness of this dietary indole against various tumors types.