Abstract
3,3′-Diindolylmethane (DIM) is a naturally derived chemopreventive compound. It comes from glucobrassicin, an indole glucosinolate enriched in cruciferous vegetables, and is formed in the acidic environment of the stomach after ingestion. Mouse double minute 2 homolog (MDM2) is an important, multi-functional oncogenic protein and it has been well recognized for its negative regulation of the tumor suppressor protein p53. We discovered a novel mechanism of action of DIM, that it directly inhibits MDM2 in multiple colorectal cancer (CRC) cell lines. Treatment with DIM decreased MDM2 at messenger RNA (mRNA) and protein levels, inhibited cancer cell proliferation, and induced cell cycle arrest and apoptosis. DIM-induced decrease of MDM2 is p53-independent and is partly mediated by proteasome degradation of MDM2, as blocking of the proteasome activity reversed MDM2 protein inhibition. Overexpression of MDM2 blocked DIM’s effects in growth suppression and apoptosis induction. When combined with imidazoline MDM2 inhibitors (Nutlin-3a and Idasanutlin/RG-7388), synergism was observed in cancer cell growth inhibition. In summary, our data support a new mechanism of action for DIM in direct inhibition of MDM2. The identification of MDM2 as a novel DIM target may help develop a new strategy in CRC prevention.
Highlights
Colorectal cancer (CRC) is a gastrointestinal malignancy that combines both colon and rectal cancers because of the shared clinical features
ODuMr2reinsuhlitbsiatolsros,sahopwotesnyntiearlgtihsteicraapnetui-tciacnscterrategy for CRacCti.vity when DIM is combined with cis-imidazoline Mouse double minute 2 homolog (MDM2) inhibitors, a potential therapeutic strategy for CRC
MDM2 is inhibited by DIM at both messenger RNA (mRNA) expression level and protein level through proteasome-mediated proteolysis
Summary
Colorectal cancer (CRC) is a gastrointestinal malignancy that combines both colon and rectal cancers because of the shared clinical features. It is the third most common malignant disease globally, with an overall 5-year survival of 64%. While chemotherapy drugs kill rapidly dividing cells and exhibit high toxicities, monoclonal antibodies and tyrosine kinase inhibitors (TKIs) are designed to target receptors on cancer cells, such as the epidermal growth factor receptor (EGFR) and several oncogenic receptors such as tyrosine kinase (RTK) [2,3,4]. ODuMr2reinsuhlitbsiatolsros,sahopwotesnyntiearlgtihsteicraapnetui-tciacnscterrategy for CRacCti.vity when DIM is combined with cis-imidazoline MDM2 inhibitors, a potential therapeutic strategy for CRC
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