Yes is a central mediator of cell growth in malignant mesothelioma cells

Sato, Ayami; Sekine, Miki; Virgona, Nantiga; M, Ota; Yano, Tomohiro

doi:10.3892/or.2012.2010

Cited by 26 publications

(26 citation statements)

References 25 publications

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“…20) Moreover, we have reported that Yes but not c-Src is a central role in determining malignancy of MM cells. 14) Overall, it is considered that the activation of Yes/HIF-2α by CoCl 2 treat- ment is associated with VEGF overexpression in H2452 cells.…”

Section: Discussionmentioning

confidence: 99%

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A Redox-Silent Analogue of Tocotrienol Inhibits Cobalt(II) Chloride-Induced VEGF Expression <i>via</i> Yes Signaling in Mesothelioma Cells

Sato

Virgona

Andõ

et al. 2014

Biological & Pharmaceutical Bulletin

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Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis and represents an attractive anticancer target. We have previously demonstrated that a redox-silent analogue of α-tocotrienol, 6-O-carboxypropyl-α-tocotrienol (T3E) exhibits potent anti-carcinogenic property in human malignant mesothelioma (MM) cells. However, inhibition of tumor growth by targeting VEGF pathway remains undetermined. In this study, we explored the inhibitory effect of T3E on the paracrine secretion of VEGF in MM cells under mimicked hypoxia by cobalt chloride (CoCl 2 ). In this study we examine whether T3E can suppress the secretion of VEGF in MM cells exposed to mimic hypoxia by cobalt chloride (CoCl 2 ). We found that CoCl 2 -induced hypoxia treatment leads to increased up-regulated hypoxia-inducible factor-2α (HIF-2α) and subsequently induced the secretion of VEGF in MM cells. This up-regulation activation mainly depended on the activation of Yes, a member of the Src family of kinases. Treatment of hypoxic MM cells with T3E effectively inhibited the secretion of VEGF, On the other hand, T3E inhibited CoCl 2 -induced gene expression of VEGF due to the inactivation of Yes/HIF-2α signaling. These data suggest that Yes/HIF2-α/VEGF could be a promising therapeutic target of T3E in MM cells.

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Section: Discussionmentioning

confidence: 99%

“…More recently, Yes, a member of SFK has been reported to be a central mediator of cell growth in MM cells. 14) As the VEGF and HIF pathways are intertwined to promote angiogenesis and tumor growth, targeting Yes/HIF-2α/VEGF signal pathway may represent a viable anticancer therapeutic target for MM.…”

mentioning

confidence: 99%

A Redox-Silent Analogue of Tocotrienol Inhibits Cobalt(II) Chloride-Induced VEGF Expression <i>via</i> Yes Signaling in Mesothelioma Cells

Sato

Virgona

Andõ

et al. 2014

Biological & Pharmaceutical Bulletin

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“…Additionally, we revealed that Yes, a member of the Src family kinases, is a central mediator in MM cell growth [24], and showed that T3E inhibits hypoxia-induced VEGF secretion via Yes signaling in MM cells [25]. Furthermore, to identify the main signal molecule involved in the anti-MM effect of T3E, comprehensive gene expression analysis was carried out using a DNA microarray.…”

Section: Discussionmentioning

confidence: 99%

A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells

et al. 2018

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Background: Wnt signaling plays an essential role in tumor cell growth, including the development of malignant mesothelioma (MM). Epigenetic silencing of negative Wnt regulators leading to constitutive Wnt signaling has been observed in various cancers and warrants further attention. We have reported that a succinate ether derivative of α-tocotrienol (T3E) has potent cytotoxic effects in MM cells. Thus, in this study, we investigated whether the anti-MM effect of T3E could be mediated via the epigenetic alteration of the Wnt antagonist gene, Dickkopf-1 (DKK1). Methods: WST-1 and cell analyzers were employed to analyze the effects of T3E on cell viability and apoptosis of human MM cell lines (H2452, H28). Real-time PCR and Western blot were performed to evaluate the expression at mRNA and protein levels. Methylation status and epigenetic modifications of DKK1’s promoter regions after T3E treatment in MM cells were studied using methylation-specific PCR and Chromatin immunoprecipitation. Small interfering RNA-mediated knockdown (siRNA), and specific inhibitors, were used to validate DKK1 as a target of T3E. Results: T3E markedly impaired MM cell viability, increased the expression of phosphorylated-JNK and DKK1 and suppressed cyclin D, a downstream target gene of Wnt signaling. Knockdown of DKK1 expression by siRNA or a specific JNK inhibitor confirmed the contribution of DKK1 and JNK to T3E-induced cytotoxicity in MM cells. On the other hand, cytoskeleton-associated protein 4 (CKAP4) expression, which promotes cell proliferation as a Wnt-independent DKK1 receptor was inhibited by T3E. Silencing CKAP4 by siRNA did not appear to directly affect MM cell viability, thereby indicating that expression of both DKK1 and CKAP4 is required. Furthermore, T3E-mediated inhibition of both DNA methyltransferases (DNMT1, 3A, and 3B) and histone deacetylases (HDAC1, 2, 3, and 8) in MM cells leads to increased DKK1 expression, thereby promoting tumor growth inhibition. MM cells treated with Zebularine (a DNMT inhibitor) and sodium butyrate (an HDAC inhibitor) exhibited cytotoxic effects, which may explain the inhibitory action of T3E on MM cells. In addition, an enhanced expression of DKK1 in MM cells following T3E treatment is positively correlated with the methylation status of its promoter; T3E decreased DNA methylation and increased histone acetylation. Moreover, T3E specifically increased histone H3 lysine 4 (H3K4) methylation activity, whereas no effects were observed on histone H3K9 and H3K27. Conclusions: Targeting the epigenetic induction of DKK1 may lead to effective treatment of MM, and T3E has great potential to induce anti-MM activity.

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“…There was downregulation of Lats2 , a downstream regulator of the Hippo pathway, which is implicated in the pathogenesis and promotion of human mesothelioma along with TGFβ (Fujii et al 2012). The oncogenes MafB and Yes were consistently upregulated in mesotheliomas from both vehicle control and VDC-exposed rats, which are mediators responsible for cell proliferation in human malignant mesotheliomas (Gordon et al 2005; Sato et al 2012). The gene expression of epithelial cell adhesion molecule ( Epcam ), a transmembrane p-glycoprotein that has multiple roles in cell signaling, migration, proliferation, and differentiation (Patriarca et al 2012), was upregulated in rat mesotheliomas.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression of Mesothelioma in Vinylidene Chloride–exposed F344/N Rats Reveal Immune Dysfunction, Tissue Damage, and Inflammation Pathways

et al. 2014

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A majority (~80%) of human malignant mesotheliomas are asbestos-related. However, non-asbestos risk factors (radiation, chemicals, genetic factors) account for up to 30% of cases. A recent two-year National Toxicology Program carcinogenicity bioassay showed that male F344/N rats exposed to the industrial toxicant vinylidene chloride (VDC) resulted in a marked increase in malignant mesothelioma. Global gene expression profiles of these tumors were compared to spontaneous mesotheliomas and the F344/N rat mesothelial cell line (Fred-PE) in order to characterize the molecular features and chemical-specific profiles of mesothelioma in VDC-exposed rats. As expected, mesotheliomas from control and vinylidene chloride-exposed rats shared pathways associated with tumorigenesis, including cellular and tissue development, organismal injury, embryonic development, inflammatory response, cell cycle regulation, and cellular growth and proliferation, while mesotheliomas from vinylidene chloride-exposed rats alone showed overrepresentation of pathways associated with pro-inflammatory pathways and immune dysfunction such as the NF-kB signaling pathway, IL-8 and IL-12 signaling, interleukin responses, Fc receptor signaling, and NK and DC signaling, as well as overrepresentation of DNA damage and repair. These data suggest that a chronic, proinflammatory environment associated with VDC exposure may exacerbate disturbances in oncogene, growth factor and cell cycle regulation, resulting in an increased incidence of mesothelioma.

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Yes is a central mediator of cell growth in malignant mesothelioma cells

Cited by 26 publications

References 25 publications

A Redox-Silent Analogue of Tocotrienol Inhibits Cobalt(II) Chloride-Induced VEGF Expression <i>via</i> Yes Signaling in Mesothelioma Cells

A Redox-Silent Analogue of Tocotrienol Inhibits Cobalt(II) Chloride-Induced VEGF Expression <i>via</i> Yes Signaling in Mesothelioma Cells

A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells

Gene Expression of Mesothelioma in Vinylidene Chloride–exposed F344/N Rats Reveal Immune Dysfunction, Tissue Damage, and Inflammation Pathways

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