Inhibition of MMP-2-mediated cellular invasion by NF-κB inhibitor DHMEQ in 3D culture of breast carcinoma MDA-MB-231 cells: A model for early phase of metastasis

Ukaji, Tamami; Lin, Yinzhi; Okada, Shoshiro; Umezawa, Kazuo

doi:10.1016/j.bbrc.2017.02.022

Cited by 21 publications

(18 citation statements)

References 18 publications

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“…We employed human breast carcinoma MDA-MB-231 cells for 3D culture. Then, we have found that 3D invasion of MDA-MB-231 cells from the colony is similar to the illustration of the early phase of metastasis shown in ( Figure 7 ) [ 34 ]. We thought it would be an ideal model for the early phase of metastasis, including the detachment and invasion of cancer cells from the primary tumor.…”

Section: Inhibition Of Late and Early Phases Of Metastasis By Dhmesupporting

confidence: 66%

Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review

Lin

Ukaji

Koide

et al. 2018

IJMS

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We previously designed and synthesized dehydroxyepoxyquinomicin (DHMEQ) as an inhibitor of NF-κB based on the structure of microbial secondary metabolite epoxyquinomicin C. DHMEQ showed anti-inflammatory and anticancer activity in various in vivo disease models without toxicity. On the other hand, the process of cancer metastasis consists of cell detachment from the primary tumor, invasion, transportation by blood or lymphatic vessels, invasion, attachment, and formation of secondary tumor. Cell detachment from the primary tumor and subsequent invasion are considered to be early phases of metastasis, while tumor cell attachment to the tissue and secondary tumor formation the late phases. The assay system for the latter phase was set up with intra-portal-vein injection of pancreatic cancer cells. Intraperitoneal administration of DHMEQ was found to inhibit liver metastasis possibly by decreasing the expression of MMP-9 and IL-8. Also, when the pancreatic cancer cells treated with DHMEQ were inoculated into the peritoneal cavity of mice, the metastatic foci formation was inhibited. These results indicate that DHMEQ is likely to inhibit the late phase of metastasis. Meanwhile, we have recently employed three-dimensional (3D) culture of breast cancer cells for the model of early phase metastasis, since the 3D invasion just includes cell detachment and invasion into the matrix. DHMEQ inhibited the 3D invasion of breast cancer cells at 3D-nontoxic concentrations. In this way, DHMEQ was shown to inhibit the late and early phases of metastasis. Thus, DHMEQ is likely to be useful for the suppression of cancer metastasis.

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Section: Inhibition Of Late and Early Phases Of Metastasis By Dhmesupporting

confidence: 66%

Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review

Lin

Ukaji

Koide

et al. 2018

IJMS

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“…In particular, massive studies had shown that MMP‐2 and MMP‐9 implied to accelerate the invasion and metastasis of BCa and were consistently associated with poor prognosis (Khan et al, 2015; Lou, Zhu, Zhao, Zhu, & Zhao, 2017; Pietruszewska, Bojanowska‐Pozniak, & Kobos, 2016; Shi et al, 2015; Sinha et al, 2016). Downregulation or loss of TIMP2 or upregulation of MMP2 commonly contributed to cancer progression such as altering migration and invasion of tumor cells (Sadot et al, 2016; Ukaji, Lin, Okada, & Umezawa, 2017; Zurac et al, 2016). Taken together, we proposed that microenvironment‐induced TIMP2 loss by cancer‐secreted exosomal miR‐4443 promoted liver metastasis of BCa.…”

Section: Discussionmentioning

confidence: 99%

Microenvironment‐induced TIMP2 loss by cancer‐secreted exosomal miR‐4443 promotes liver metastasis of breast cancer

Wang

Zhang

Wang

et al. 2020

Journal Cellular Physiology

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We aimed to investigate the role of exosomal miR‐4443 in metastasis of breast cancer (BCa). In vitro wound‐healing assay and transwell invasion assay were used to investigate effect of miR‐4443 on BCa cells. Animal experiments were performed to confirm its effects in vivo. miR‐4443 promotes the metastasis of BCa cells through downregulating tissue inhibitors of metalloproteinase 2 (TIMP2) and upregulating matrix metalloproteinases (MMPs). Highly invasive BCa cells have a higher expression of miR‐4443 in both cells and exosomes. The exosomes derived from highly invasive BCa cells mainly gather in the primary tumor and liver. In vivo, overexpression of miR‐4443 in noninvasive BCa cells induces liver metastasis, accompanied with downregulated TIMP2, and upregulated MMP‐2 in both the primary tumor and liver. When we armed MCF‐10A exosomes with miR‐4443 inhibitors to treat mice bearing high‐miR‐4443 tumors, exosomes accumulated in the primary tumor, and liver following the upregulation of TIMP2 and downregulation of MMP2, and the metastasis was inhibited. Highly invasive BCa cells destroy natural barriers against metastasis by delivering exosomal miR‐4443 to stromal cells of the primary tumor and impairing TIMP2, consequently activating MMP; circulating exosomal miR‐4443 might promote BCa cells lodging in future metastatic sites through the similar mechanisms.

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“…MDA-MB-231 cells were trypsinized and resuspended in serum free media at a density of 1 × 10 7 /mL and implanted into the mammary fat pad of the mice (200 μ L/mouse). When the volumes of xenografts reached to 100 mm 3 , mice were randomized to receive vehicle control (12 mice per group) or tested compounds (six mice per group).…”

Section: Methodsmentioning

confidence: 99%

“…7-10 Therefore, additional research of MMPs has focused on their regulation in an effort to identify other potential drug target candidates. Asparagine endopeptidase (AEP, legumain) was found to activate MMP-2 by proteolytic removal of an N-terminal propeptide.…”

Section: Introductionmentioning

confidence: 99%

Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis

Obianyo

et al. 2017

J. Med. Chem.

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Asparagine endopeptidase (AEP), also called legumain, is highly expressed in various solid tumors, promoting cancer cell invasion, migration, and metastasis. It has been proposed to be a prognostic marker and therapeutic target for cancer treatment. However, an effective nonpeptide, smallmolecule inhibitor against this protease has not yet been identified. Here we show that a family of xanthine derivatives selectively inhibit AEP and suppress matrix metalloproteinase (MMP) cleavage, leading to the inhibition of cancer metastasis. Through structure–activity relationship (SAR) analysis, we obtained an optimized lead compound (38u) that represses breast cancer invasion and migration. Chronic treatment of nude mice, which had been inoculated with MDA-MB-231 cells, with inhibitor 38u via oral administration robustly inhibits breast cancer lung metastasis in a dose-dependent manner, associated with blockade of MMP-2 by AEP. Therefore, our study supports that 38u might act as a potent and specific AEP inhibitor useful for cancer treatment.

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Inhibition of MMP-2-mediated cellular invasion by NF-κB inhibitor DHMEQ in 3D culture of breast carcinoma MDA-MB-231 cells: A model for early phase of metastasis

Cited by 21 publications

References 18 publications

Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review

Inhibition of Late and Early Phases of Cancer Metastasis by the NF-κB Inhibitor DHMEQ Derived from Microbial Bioactive Metabolite Epoxyquinomicin: A Review

Microenvironment‐induced TIMP2 loss by cancer‐secreted exosomal miR‐4443 promotes liver metastasis of breast cancer

Blockade of Asparagine Endopeptidase Inhibits Cancer Metastasis

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