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Modulation of the HGF/c-Met/Akt and p38 cell signaling pathways by 3,3'-diindolylmethane in MDA-MB-231 breast cancer cells


Cancer is a leading cause of death worldwide, with cancer deaths expected to continue to rise, necessitating new prevention and treatment strategies. Bioactive food components like Brassica-derived 3,3'-diindolylmethane (DIM) are a promising area of study for cancer prevention and treatment. Due to its efficacy, availability, low cost, and low toxicity, DIM is currently in use as a treatment for recurrent respiratory papillomatosis and is in clinical trials for the prevention and treatment of prostate and cervical cancers.

DIM's anticancer activities include induction of cell cycle arrest and apoptosis, inhibition of angiogenesis, and immune activation. Though some mechanisms for these activities in various cancer cells have been uncovered, it is clear that DIM works through multiple pathways. More research is necessary to determine the full extent of DIM's effects and to identify specific cellular targets of DIM. This dissertation focuses on DIM's effects on the signaling pathways of two specific pathways, HGF/c-Met/Akt and p38 MAPK.

Akt signaling is frequently dysregulated in breast cancer. Although it has been reported that DIM inhibits Akt signaling in breast cancer cells, the mechanism(s) for this action, as well as the kinetics and effects of lower, physiologically relevant concentrations of DIM, have remained unknown. In chapter 2 we demonstrate that physiologically relevant concentrations of DIM inhibit short- and long-term activation of Akt in the highly invasive MDA-MB-231 breast cancer cells. DIM also selectively inhibits HGF-induced Akt activation, which is one novel mechanism by which DIM inhibits Akt. In addition, DIM inhibits cell cycle progression and in vitro metastasis and induced apoptosis, which are all consistent with Akt inhibition.

The roles of specific upstream activators of the Akt pathway, including c-Met, in this activity have not been investigated. In chapter 3, we demonstrate that DIM inhibits motility and proliferation of MDA-MB-231 breast cancer cells downstream of HGF, and that DIM promotes ligand-dependent degradation of c-Met and inhibits c-Met activation.

Even with its strong inhibition by DIM, the Akt pathway is just one of several signaling pathways modified by DIM. DIM also exerts some of its anti-cancer effects by activating the p38 pathway. DIM activates p38 in various cancer cells, including breast cancer cells, and that p38 activation as well as regulation of expression of various genes have been shown to play a role in DIM's effects in breast cancer cells. However, the connection between these two effects has not been reported. In chapter 4 we demonstrate through gene expression profiling that 25 μM DIM for 4 hours regulates the expression of over 400 genes in MDA-MB-231 cells. We also show that DIM activates p38 under physiologically relevant conditions and this activation is partly responsible for DIM-induced up regulation of several genes and for DIM's induction of apoptosis.

Future experiments should focus on determining a specific mechanism by which DIM inhibits c-Met and should establish the relationship between c-Met inhibition and Akt inhibition, as well as between c-Met/Akt inhibition and cell cycle progression, proliferation, apoptosis, and motility in MDA-MB-231 breast cancer cells. The results of the gene expression profiling study also provide many opportunities for follow up experiments.

In summary, DIM is a promising anti-breast cancer compound that exerts its effects in part by inhibiting the HGF/c-Met/Akt pathway and by activating the p38 pathway.

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