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Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells

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-f...

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Autores principales: Gao, Xiang, Liu, Jingwen, Cho, Kwang Bog, Kedika, Samanthreddy, Guo, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370074/
https://www.ncbi.nlm.nih.gov/pubmed/32629830
http://dx.doi.org/10.3390/ijms21134642
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author Gao, Xiang
Liu, Jingwen
Cho, Kwang Bog
Kedika, Samanthreddy
Guo, Bin
author_facet Gao, Xiang
Liu, Jingwen
Cho, Kwang Bog
Kedika, Samanthreddy
Guo, Bin
author_sort Gao, Xiang
collection PubMed
description 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.
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spelling pubmed-73700742020-07-21 Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells Gao, Xiang Liu, Jingwen Cho, Kwang Bog Kedika, Samanthreddy Guo, Bin Int J Mol Sci Article 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. MDPI 2020-06-30 /pmc/articles/PMC7370074/ /pubmed/32629830 http://dx.doi.org/10.3390/ijms21134642 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gao, Xiang
Liu, Jingwen
Cho, Kwang Bog
Kedika, Samanthreddy
Guo, Bin
Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells
title Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells
title_full Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells
title_fullStr Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells
title_full_unstemmed Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells
title_short Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells
title_sort chemopreventive agent 3,3′-diindolylmethane inhibits mdm2 in colorectal cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370074/
https://www.ncbi.nlm.nih.gov/pubmed/32629830
http://dx.doi.org/10.3390/ijms21134642
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