IL6-induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in ovarian cancer cells.

PURPOSE: Ovarian cancer is a highly lethal gynecological malignancy for which the overall prognosis has remained poor over the past few decades. Interleukin (IL6) has been found to be a major contributor to the initiation and progression of ovarian cancer. This cytokine exerts its activity through activation of several signaling pathways, in particular the signal transducer and activator of transcription (STAT3) pathway. Here, we aimed at investigating the capacity of a natural dietary compound found in cruciferous vegetables, i.e., 3,3'-diindolylmethane (DIM), to target the metastatic phenotype of ovarian cancer cells through functional p-STAT3.

METHODS

The human ovarian carcinoma-derived cell lines SKOV3 and A2780 were treated with IL6 and/or DIM and subjected to in vitro proliferation, adhesion, migration and invasion assays to assess the anti-metastatic and anti-IL6 effects of DIM, as well as to assess gene expression alterations before and after shRNA-mediated STAT3 silencing.

RESULTS

We found that DIM inhibits IL6-mediated increases in ovarian cancer cell adhesion, migration and invasion. These results were corroborated by shRNA-mediated STAT3 silencing. Through Western blot and ELISA analyses direct evidence was provided for the capacity of DIM to inhibit ovarian cancer cell adhesion, migration and invasion, which was found to be associated with down-regulation of the matrix metalloproteinases MMP-2 and MMP-9.

CONCLUSIONS

From our data we conclude that DIM exhibits an anti-IL6-like activity by inhibiting p-STAT3 enhanced ovarian cancer cell proliferation and in vitro metastasis-associated events, i.e., adhesion, migration and invasion. Most significantly, MMP-2 and MMP-9, which are known to promote and enhance metastasis, were found to act as targets of DIM. This anti-IL6-like property of DIM may pave the way for the development of novel ovarian cancer preventive and/or therapeutic strategies.