IRGM1 enhances B16 melanoma cell metastasis through PI3K-Rac1 mediated epithelial mesenchymal transition

Juzen-Taiho-To (JTT) is well known to be one of Kampo (Japanese herbal) medicine consisted of 10 component herbs and used for the supplemental therapy of cancer patients with remarkably success. However, the precise mechanisms by which JTT could favorably modify the clinical conditions of cancer patients are not well defined. The present study, therefore, was undertaken to examine the possible mechanisms of JTT on prevention of cancer metastasis using experimental mouse model. JTT was well mixed with rodent chow at concentrations of either 0.2 or 1.0%, and administered orallyad libitum, which was started 1 week before tumor cell injection and continue throughout the experiment. Oral administration of JTT at concentration 0.2 and 1.0% into C57BL/6 male mice significantly inhibited tumor metastasis in lungs, which was induced by the intravenous injection of 2 × 105B16 melanoma cell. JTT at a concentration of 1.0% also significantly suppressed lung metastasis of B16 melanoma cell from hind footpad in C57BL/6 mice. In the second part of experiments, the influence of the depression of natural killer (NK) cell, natural killer T (NKT) cell and several types of cytokines on JTT-mediated inhibition of tumor cell metastasis. Intraperitoneal injection of anti asialo-GM1 antibody against NK cells and anti NK-1.1 monoclonal antibody (mAb) to NKT cells abrogated the inhibitory action of JTT on lung metastasis of B16 melanoma cells. Although intraperitoneal administration of anti-IFN-γ mAb scarcely affected the inhibitory action of JTT on tumor cell metastasis, injection of amrinone, which used for IL-12 suppression, significantly decreased the ability of JTT to prevent tumor cell metastasis. These results strongly suggest that oral administration of JTT caused increase in the production of IL-12, which is responsible for the activation of both NK cell and NKT cell, in the lungs and results in inhibition of B16 melanoma cell metastasis in the lungs.

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LRIG1 acts as a critical regulator of melanoma cell invasion, migration, and vasculogenic mimicry upon hypoxia by regulating EGFR/ERK-triggered epithelial–mesenchymal transition

Bioscience Reports ◽

10.1042/bsr20181165 ◽

2019 ◽

Vol 39 (1) ◽

Cited By ~ 7

Author(s):

Wei Li ◽

Yubo Zhou

Keyword(s):

Melanoma Cell ◽

Cell Invasion ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Vasculogenic Mimicry ◽

Growth Factor Receptor ◽

Inhibition Mechanism ◽

Mechanism Analysis ◽

Mesenchymal Transition ◽

Hypoxia Exposure

AbstractIntratumoral hypoxia is a well-known feature of solid cancers and constitutes a major contributor to cancer metastasis and poor outcomes including melanoma. Leucine-rich repeats and Ig-like domains 1 (LRIG1) participate in the aggressive progression of several tumors, where its expression is frequently decreased. In the present study, hypoxia exposure aggravated melanoma cell invasion, migration, vasculogenic mimicry (VM), and epithelial–mesenchymal transition (EMT). During this process, LRIG1 expression was also decreased. Importantly, overexpression of LRIG1 notably counteracted hypoxia-induced invasion, migration, and VM, which was further augmented after LRIG1 inhibition. Mechanism analysis corroborated that LRIG1 elevation muted hypoxia-induced EMT by suppressing E-cadherin expression and increasing N-cadherin expression. Conversely, cessation of LRIG1 further potentiated hypoxia-triggered EMT. Additionally, hypoxia stimulation activated the epidermal growth factor receptor (EGFR)/ERK pathway, which was dampened by LRIG1 up-regulation but further activated by LRIG1 inhibition. More important, blocking this pathway with its antagonist erlotinib abrogated LRIG1 suppression-induced EMT, and subsequently cell invasion, migration, and VM of melanoma cells under hypoxia. Together, these findings suggest that LRIG1 overexpression can antagonize hypoxia-evoked aggressive metastatic phenotype by suppressing cell invasion, migration, and VM via regulating EGFR/ERK-mediated EMT process. Therefore, these findings may provide a promising target for melanoma therapy.

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Activation of AMP-activated protein kinase is involved in vincristine-induced cell apoptosis in B16 melanoma cell

Journal of Cellular Physiology ◽

10.1002/jcp.22522 ◽

2011 ◽

Vol 226 (7) ◽

pp. 1915-1925 ◽

Cited By ~ 69

Author(s):

Min-Bin Chen ◽

Wen-Xiang Shen ◽

Yun Yang ◽

Xiao-Yang Wu ◽

Jin-Hua Gu ◽

...

Keyword(s):

Protein Kinase ◽

Melanoma Cell ◽

Cell Apoptosis ◽

B16 Melanoma ◽

B16 Melanoma Cell ◽

Amp Activated Protein Kinase

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Nimotuzumab Inhibits Cholangiocarcinoma Cell Metastasis via Suppression of the Epithelial–Mesenchymal Transition Process

Anticancer Research ◽

10.21873/anticanres.11729 ◽

2017 ◽

Vol 37 (7) ◽

Cited By ~ 2

Keyword(s):

Epithelial Mesenchymal Transition ◽

Transition Process ◽

Mesenchymal Transition ◽

Cell Metastasis ◽

Cholangiocarcinoma Cell

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NEDD9 may regulate hepatocellular carcinoma cell metastasis by promoting epithelial-mesenchymal-transition and stemness via repressing Smad7

Oncotarget ◽

10.18632/oncotarget.13852 ◽

2016 ◽

Vol 8 (1) ◽

pp. 1714-1724 ◽

Cited By ~ 13

Author(s):

Zhipeng Wang ◽

Min Shen ◽

Peng Lu ◽

Xiao Li ◽

Shaojun Zhu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Carcinoma Cell ◽

Mesenchymal Transition ◽

Cell Metastasis ◽

Hepatocellular Carcinoma Cell

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Bornyl cis-4-Hydroxycinnamate Suppresses Cell Metastasis of Melanoma through FAK/PI3K/Akt/mTOR and MAPK Signaling Pathways and Inhibition of the Epithelial-to-Mesenchymal Transition

International Journal of Molecular Sciences ◽

10.3390/ijms19082152 ◽

2018 ◽

Vol 19 (8) ◽

pp. 2152 ◽

Cited By ~ 8

Author(s):

Tzu-Yen Yang ◽

Mei-Li Wu ◽

Chi-I Chang ◽

Chih-I Liu ◽

Te-Chih Cheng ◽

...

Keyword(s):

Cell Migration ◽

Signaling Pathways ◽

Melanoma Cell ◽

Epithelial To Mesenchymal Transition ◽

Melanoma Cells ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Cell Migration And Invasion ◽

Cell Metastasis ◽

A375 Melanoma

Bornyl cis-4-hydroxycinnamate, a bioactive compound isolated from Piper betle stems, has the potential for use as an anti-cancer agent. This study investigated the effects of bornyl cis-4-hydroxycinnamate on cell migration and invasion in melanoma cells. Cell migration and invasion were compared in A2058 and A375 melanoma cell lines treated with/without bornyl cis-4-hydroxycinnamate (1–6 µM). To examine whether bornyl cis-4-hydroxycinnamate has a potential anti-metastatic effect on melanoma cells, cell migration and invasion assays were performed using a Boyden chamber assay and a transwell chamber in A2058 and A375 cells. Gelatin zymography was employed to determine the enzyme activities of MMP-2 and MMP-9. Cell lysates were collected for Western blotting analysis of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors of metalloproteinase-1/2 (TIMP-1/2), as well as key molecules in the mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK)/ phosphatidylinositide-3 kinases (PI3K)/Akt/ mammalian target of rapamycin (mTOR), growth factor receptor-bound protein 2 (GRB2) signaling pathways. Our results demonstrated that bornyl cis-4-hydroxycinnamate is a potentially useful agent that inhibits melanoma cell migration and invasion, and altered melanoma cell metastasis by reducing MMP-2 and MMP-9 expression through inhibition of the FAK/PI3K/Akt/mTOR, MAPK, and GRB2 signaling pathways. Moreover, bornyl cis-4-hydroxycinnamate inhibited the process of the epithelial-to-mesenchymal transition in A2058 and A375 melanoma cells. These findings suggested that bornyl cis-4-hydroxycinnamate has potential as a chemotherapeutic agent, and warrants further investigation for its use in the management of human melanoma.

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