Genome-wide transcriptome analysis reveals inactivation of Wnt/β-catenin by 3,3′-diindolylmethane inhibiting proliferation of colon cancer cells

Leem, Sun‐Hee; Li, Xiu Juan; Park, Man Hee; Park, Byung Hyun; Kim, Soo Mi

doi:10.3892/ijo.2015.3089

Cited by 23 publications

(14 citation statements)

References 39 publications

(42 reference statements)

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“…They not only regulates RA-FLSs growth, apoptosis and differentiation but also are critical for synovial inflammation and joint destruction in inflammatory arthritis (15, 41). There were other reports that DIM inhibited cell growth by downregulation of Akt/FoxM1 signaling pathway in gastric cancer (46), by inactivation of β-catenin/c-Myc in colorectal cancer (47). These results suggest that DIM might possess a cell type-specific function in modulating cell growth.…”

Section: Discussionmentioning

confidence: 99%

A Novel Phytochemical, DIM, Inhibits Proliferation, Migration, Invasion and TNF-α Induced Inflammatory Cytokine Production of Synovial Fibroblasts From Rheumatoid Arthritis Patients by Targeting MAPK and AKT/mTOR Signal Pathway

Zhang

Zeng

et al. 2019

Front. Immunol.

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In rheumatoid arthritis(RA) pathogenesis, activated RA fibroblast-like synoviocytes (RA-FLSs) exhibit similar proliferative features as tumor cells and subsequent erosion to cartilage will eventually lead to joint destruction. Therefore, it is imperative to search for compounds, which can effectively inhibit the abnormal activation of RA-FLSs, and retard RA progression.3′3-Diindolylmethane (DIM), the major product of the acid-catalyzed oligomerization of indole-3-carbinol from cruciferous vegetables, has been reported to be functionally relevant to inhibition of migration, invasion and carcinogenesis in some solid tumors. In this study, we explored the anti-proliferation, anti-metastasis and anti-inflammation effects of DIM on RA-FLSs as well as the underlying molecular mechanisms. To do this, primary RA-FLSs were isolated from RA patients and an animal model. Cell proliferation, migration and invasion were measured using CCK-8, scratch, and Transwell assays, respectively. The effects of DIM on Matrix metalloproteinases (MMPs) and some inflammatory factors mRNA and key molecules such as some inflammatory factors and those involved in aberrantly-activated signaling pathway in response to tumor necrosis factor α(TNF-α), a typical characteristic mediator in RA-FLS, were quantitatively measured by real-time PCR and western blotting. Moreover, the effect of DIM on adjuvant induced arthritis(AIA) models was evaluated with C57BL/6 mice in vivo . The results showed that DIM inhibited proliferation, migration and invasion of RA-FLS in vitro . Meanwhile, DIM dramatically suppressed TNF-α–induced increases in the mRNA levels of MMP-2, MMP-3, MMP-8 , and MMP-9 ; as well as the proinflammatory factors IL-6, IL-8 , and IL-1 β. Mechanistic studies revealed that DIM is able to suppress phosphorylated activation not only of p38, JNK in MAPK pathway but of AKT, mTOR and downstream molecules in the AKT/mTOR pathway. Moreover, DIM treatment decreased expression levels of proinflammatory cytokines in the serum and alleviated arthritis severity in the knee joints of AIA mice. Taken together, our findings demonstrate that DIM could inhibit proliferation, migration and invasion of RA-FLSs and reduce proinflammatory factors induced by TNF-α in vitro by blocking MAPK and AKT/mTOR pathway and prevent inflammation and knee joint destruction in vivo , which suggests that DIM might have therapeutic potential for RA.

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Section: Discussionmentioning

confidence: 99%

A Novel Phytochemical, DIM, Inhibits Proliferation, Migration, Invasion and TNF-α Induced Inflammatory Cytokine Production of Synovial Fibroblasts From Rheumatoid Arthritis Patients by Targeting MAPK and AKT/mTOR Signal Pathway

Zhang

Zeng

et al. 2019

Front. Immunol.

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“…16,[86][87][88] Altered expression or activity of β-catenin has been implicated in regulating proliferation 28,84 and oncogenesis 22,33,75,[89][90][91] being proposed as a 'co-factor' in the initiation of EMT. 92,93 Inhibition of the Wnt/β-catenin pathway inhibits cancer cell proliferation 31,94,95 although others have linked β-catenin activation to reduced growth and increased differentiation. 96 The levels of β-catenin expression may be different in a range of tumour cells types.…”

Section: β-Cateninmentioning

confidence: 99%

Serine protease modulation of Dependence Receptors and EMT protein expression

McNair

Forrest

Vincenten

et al. 2018

Cancer Biology & Therapy

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Expression of the tumour suppressor Deleted in Colorectal Cancer (DCC) and the related protein neogenin is reduced by the mammalian serine protease chymotrypsin or the bacterial serine protease subtilisin, with increased cell migration. The present work examines whether these actions are associated with changes in the expression of cadherins, β-catenin and vimentin, established markers of the Epithelial-Mesenchymal Transition (EMT) which has been linked with cell migration and tumour metastasis. The results confirm the depletion of DCC and neogenin and show that chymotrypsin and subtilisin also reduce expression of β-catenin in acutely prepared tissue sections but not in human mammary adenocarcinoma MCF-7 or MDA-MB-231 cells cultured in normal media, or primary normal human breast cells. A loss of β-catenin was also seen in low serum media but transfecting cells with a dcc-containing plasmid induced resistance. E-cadherin was not consistently affected but vimentin was induced by low serum-containing media and was increased by serine proteases in MCF-7 and MDA-MB-231 cells in parallel with increased wound closure. Vimentin might contribute to the promotion of cell migration. The results suggest that changes in EMT proteins depend on the cells or tissues concerned and do not parallel the expression of DCC and neogenin. The increased cell migration induced by serine proteases is not consistently associated with the expression of the EMT proteins implying either that the increased migration may be independent of EMT or supporting the view that EMT is not itself consistently related to migration. (241).

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“…A genome-wide transcriptome analysis performed in our laboratory revealed that DIM alters approximately 1424 genes related to cell proliferation, the cell cycle, and apoptosis. In addition, we found that DIM significantly downregulates β-catenin and c-Myc signaling to inhibit colon cancer cell growth ( Figure 2 ) [ 62 ]. Another study conducted by our laboratory showed that DIM significantly represses the migration and invasion of colorectal cancer cells (DLD-1 and HCT-116) [ 63 ].…”

Section: 33′-diindolylmethane and Colorectal Cancermentioning

confidence: 99%

Cellular and Molecular Mechanisms of 3,3′-Diindolylmethane in Gastrointestinal Cancer

Kim

2016

IJMS

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Studies in humans have shown that 3,3′-diindolylmethane (DIM), which is found in cruciferous vegetables, such as cabbage and broccoli, is effective in the attenuation of gastrointestinal cancers. This review presents the latest findings on the use, targets, and modes of action of DIM for the treatment of human gastrointestinal cancers. DIM acts upon several cellular and molecular processes in gastrointestinal cancer cells, including apoptosis, autophagy, invasion, cell cycle regulation, metastasis, angiogenesis, and endoplasmic reticulum (ER) stress. In addition, DIM increases the efficacy of other drugs or therapeutic chemicals when used in combinatorial treatment for gastrointestinal cancer. The studies to date offer strong evidence to support the use of DIM as an anticancer and therapeutic agent for gastrointestinal cancer. Therefore, this review provides a comprehensive understanding of the preventive and therapeutic properties of DIM in addition to its different perspective on the safety of DIM in clinical applications for the treatment of gastrointestinal cancers.

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Genome-wide transcriptome analysis reveals inactivation of Wnt/β-catenin by 3,3′-diindolylmethane inhibiting proliferation of colon cancer cells

Cited by 23 publications

References 39 publications

A Novel Phytochemical, DIM, Inhibits Proliferation, Migration, Invasion and TNF-α Induced Inflammatory Cytokine Production of Synovial Fibroblasts From Rheumatoid Arthritis Patients by Targeting MAPK and AKT/mTOR Signal Pathway

A Novel Phytochemical, DIM, Inhibits Proliferation, Migration, Invasion and TNF-α Induced Inflammatory Cytokine Production of Synovial Fibroblasts From Rheumatoid Arthritis Patients by Targeting MAPK and AKT/mTOR Signal Pathway

Serine protease modulation of Dependence Receptors and EMT protein expression

Cellular and Molecular Mechanisms of 3,3′-Diindolylmethane in Gastrointestinal Cancer

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