Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

Sakamoto, Takabumi; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Satoru; Uesato, Shinichi; Watanabe, Kazushi; Tanimura, Susumu; Koji, Takehiko; Kohno, Michiaki

doi:10.1016/j.bbrc.2013.03.009

Cited by 17 publications

(13 citation statements)

References 26 publications

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“…HBx expression significantly increased phosphorylation of Akt and ERK when compared with non-transfected or mock-transfected controls. We also found that treatment with either PI3K or MEK inhibitors, LY294002 [28,29] or PD184352 [30,31], inhibited the activation of Akt and ERK in oval cells, indicating that phosphorylation of Akt and ERK depended on the activities of PI3K and MEK. We next examined the functional involvement of the PI3K/Akt and MEK/ERK signaling pathways in HBx-induced proliferation and cyclin D1 expression.…”

Section: Resultsmentioning

confidence: 90%

HBx Protein Promotes Oval Cell Proliferation by Up-Regulation of Cyclin D1 via Activation of the MEK/ERK and PI3K/Akt Pathways

Wang

Yang

Liang

et al. 2014

IJMS

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Growing evidence has shown that hepatic oval cells, also named liver progenitor cells, play an important role in the process of liver regeneration in various liver diseases. Oval cell proliferation has been reported in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and chronic liver disease. Studies have found expression of HBV surface and core antigens in oval cells in the livers of patients with HCC, suggesting that HBV infection of oval cells could be a mechanism of human hepatocarcinogenesis. In addition, there is evidence of multiplication of HBV in oval cell culture. However, little research has been performed to explore the role of HBV-encoded proteins in the proliferation of hepatic oval cells. Previously, we successfully transfected the HBV x (HBx) gene, one of the four genes in the HBV genome, into a rat LE/6 oval cell line. In this study, we tested whether or not the transfected HBx gene could affect oval cell proliferation in vitro. Our results show that overexpression of HBx promotes the proliferation of oval cells and increases cyclin D1 expression, assessed at both the mRNA and protein levels. We also found that HBx activated the PI-3K/Akt and MEK/ERK1/2 pathways in HBx-transfected oval cells. Furthermore, the HBx-induced increases in cyclin D1 expression and oval cell proliferation were completely abolished by treatment with either MEK inhibitor PD184352 or PI-3K inhibitor LY294002. These results demonstrated that HBx has the ability to promote oval cell proliferation in vitro, and its stimulatory effects on cell proliferation and expression of cyclin D1 depend on the activation of the MEK/ERK and PI3K/Akt signaling pathways in cultured oval cells.

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Section: Resultsmentioning

confidence: 90%

HBx Protein Promotes Oval Cell Proliferation by Up-Regulation of Cyclin D1 via Activation of the MEK/ERK and PI3K/Akt Pathways

Wang

Yang

Liang

et al. 2014

IJMS

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“…18 Blockade of the ERK pathway sensitized tumor xenografts to the cytotoxicity of histone deacetylase inhibitor MS-275 in vivo. 19 However, some studies have shown that ERK1/2 inactivation by ERK1/2 inhibitor markedly blocked cisplatin-induced apoptosis in human malignant testicular germ cells. 20 In view of these facts, we further investigate the possible potential links between Notch be activated by growth stimuli and generally acts as a prosurvival mediator.…”

Section: Discussionmentioning

confidence: 99%

Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin

Yao

Qian

Shu

et al. 2013

Cancer Biology & Therapy

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“…6,7 Previous study has identified that EMT/ ERK can promote growth, invasion, and metastasis of cancer, which may play important role in multiple more aggressive tumor cells by endowing cells with a more motile and invasive potential. 8 High mobility group AT-hook 2 (HMGA2) is a chromatin remodeling factor that can change the chromatin architecture to regulate the activity of transcriptional enhancers. 9 Previous study has showed that HMGA2 evidences as an architectural transcription factor, which is related with progression and prognosis of many malignant cancers.…”

Section: Introductionmentioning

confidence: 99%

Angiotensin II type 2 receptor–interacting protein 3a inhibits ovarian carcinoma metastasis via the extracellular HMGA2-mediated ERK/EMT pathway

Huang

Guo

et al. 2017

Tumour Biol.

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Local migration and long-distance metastasis is the main reason for higher mortality of ovarian cancer. Microtubule-associated tumor suppressor 1/angiotensin II type 2 receptor-interacting protein is associated with tumor initiation and progression and exerts anti-tumor effects. High mobility group AT-hook 2 is overexpressed in majority of metastatic carcinomas, which contributes to carcinomas metastasis through Snail-induced epithelial-to-mesenchymal transition signal pathway. The purpose of this study was to investigate the signal pathway of microtubule-associated tumor suppressor 1/angiotensin II type 2 receptor-interacting protein-mediated anti-tumor effects. Our data observed that ovarian carcinoma cells exhibited lower expression of angiotensin II type 2 receptor-interacting protein 3a and higher expression of high mobility group AT-hook 2 compared to normal ovarian cells. Restoration of angiotensin II type 2 receptor-interacting protein 3a expression in ovarian carcinoma cells inhibited high mobility group AT-hook 2 expression and exhibited anti-proliferative effects. In addition, angiotensin II type 2 receptor-interacting protein 3a treatment suppressed the phosphorylation of epithelial-to-mesenchymal transition and extracellular signal-regulated kinase in ovarian carcinoma cells. We also observed that angiotensin II type 2 receptor-interacting protein 3a restoration downregulated expression of Snail, E-Cadherin, N-Cadherin, and Vimentin in ovarian carcinoma cells, whereas angiotensin II type 2 receptor-interacting protein 3a knockdown enhanced the phosphorylation of extracellular signal-regulated kinase and epithelial-to-mesenchymal transition. In vivo assay indicated that angiotensin II type 2 receptor-interacting protein 3a inhibited ovarian tumor growth and elevated survival of tumor-bearing immunodeficient mice. Tumor histological analysis indicated that Snail, E-Cadherin, N-Cadherin, and Vimentin expression levels were downregulated via decreasing high mobility group AT-hook 2 expression. Furthermore, upregulation of angiotensin II type 2 receptor-interacting protein 3a impaired the phenotype of extracellular signal-regulated kinase and epithelial-to-mesenchymal transition in ovarian carcinoma cells and tumor tissues. Taken together, angiotensin II type 2 receptor-interacting protein 3a presents potential in suppressing the proliferation and aggressiveness of ovarian carcinoma cells through the high mobility group AT-hook 2-mediated extracellular signal-regulated kinase/epithelial-to-mesenchymal transition signal pathway.

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Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

Cited by 17 publications

References 26 publications

HBx Protein Promotes Oval Cell Proliferation by Up-Regulation of Cyclin D1 via Activation of the MEK/ERK and PI3K/Akt Pathways

HBx Protein Promotes Oval Cell Proliferation by Up-Regulation of Cyclin D1 via Activation of the MEK/ERK and PI3K/Akt Pathways

Combination treatment of PD98059 and DAPT in gastric cancer through induction of apoptosis and downregulation of WNT/β-catenin

Angiotensin II type 2 receptor–interacting protein 3a inhibits ovarian carcinoma metastasis via the extracellular HMGA2-mediated ERK/EMT pathway

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