Pterostilbene Exerts Antitumor Activity via the Notch1 Signaling Pathway in Human Lung Adenocarcinoma Cells
Yang YangXiaolong YanWeixun DuanJuanjuan YanWei YiZhenxin LiangNing WangYue LiWensheng ChenShiqiang YuZhenxiao JinDinghua Yi
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Although pterostilbene (PTE) has been shown to have potent antitumor activities against various cancer types, the molecular mechanisms of these activities remain unclear. In this study, we investigated the antitumor activity of PTE against human lung adenocarcinoma in vitro and in vivo and explored the role of the Notch1 signaling pathway in this process. PTE treatment resulted in a dose- and time-dependent decrease in the viability of A549 cells. Additionally, PTE exhibited strong antitumor activity, as evidenced not only by a reduced mitochondrial membrane potential (MMP) and a decreased intracellular glutathione content but also by increases in the apoptotic index and the level of reactive oxygen species (ROS). Furthermore, PTE treatment induced the activation of the Notch1 Intracellular Domain (NICD) protein and activated Hes1. DAPT (a gamma secretase inhibitor) and Notch1 siRNA prevented the induction of NICD and Hes1 activation by PTE treatment and sensitized the cells to PTE treatment. The down-regulation of Notch signaling also prevented the activation of pro-survival pathways (most notably the PI3K/Akt pathway) after PTE treatment. In summary, lung adenocarcinoma cells may enhance Notch1 activation as a protective mechanism in response to PTE treatment. Combining a gamma secretase inhibitor with PTE treatment may represent a novel approach for treating lung adenocarcinoma by inhibiting the survival pathways of cancer cells.Keywords:
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Pterostilbene
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Hes3 signaling axis
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Abstract Notch can act as an oncogene or as a tumor suppressor and thus can either promote or inhibit tumor cell growth. To establish Notch status in Ewing's sarcoma family of tumors (ESFT), we investigated the Notch pathway by gene expression profiling meta-analysis or immunohistochemistry in samples obtained from 96 and 24 ESFT patients, respectively. We find that although Notch receptors were highly expressed, Notch did not appear to be active as evidenced by the absence of Notch receptors in cell nuclei. High expression of the Notch effector HES1 transcription factor, usually used as a surrogate marker for active Notch, was also restricted to outside of the nucleus in the majority of tumors, and analysis of HES1 gene targets indicated HES1 to be transcriptionally inactive. Neither forced activation nor pharmacological or genetic blocking of Notch affected HES1 expression in ESFT cells, indicating HES1 expression to be uncoupled from the Notch pathway. Additional functional studies in ESFT cell lines confirmed Notch to be switched off. Finally, unlike experiments in which HES1 expression was modulated, experimental activation of Notch in ESFT cell lines via several means blocked cell proliferation. These indicate that HES1 is uncoupled from Notch in ESFT, that EWS-FLI1-mediated inhibition of Notch contributes to ESFT aggressive cell growth, and supports a role for Notch in ESFT tumor suppression, at least partly through the Notch effector HEY1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1936. doi:10.1158/1538-7445.AM2011-1936
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In the developing nervous system, the expression of proneural genes, i.e., Hes1, Neurogenin-2 (Ngn2), and Deltalike-1 (Dll1), oscillates in neural progenitors with a period of 2–3 h, but is persistent in postmitotic neurons. In this paper, we present a computational model for neural fate decisions based on intertwined Notch-Delta signaling involving the Hes1, Notch, and Dll1 proteins. In agreement with experimental observations, the model predicts that Notch-Delta signaling plays critical roles in regulating the choice between remaining as a progenitor and embarking on neural differentiation.
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Abstract Notch can act as an oncogene or as a tumour suppressor and thus can either promote or inhibit tumour cell growth. To establish Notch status in Ewing's sarcoma family of tumours (ESFT), we investigated the Notch pathway by gene expression profiling meta‐analysis or immunohistochemistry in samples obtained from 96 and 24 ESFT patients, respectively. We found that although Notch receptors were highly expressed, Notch did not appear to be active, as evidenced by the absence of Notch receptors in cell nuclei. In contrast, we show that Notch receptors known to be active in colon adenocarcinoma, hepatocarcinoma, and pancreatic carcinoma stain cell nuclei in these tumours. High expression of the Notch effector HES1 transcription factor, usually used as a surrogate marker for active Notch, was also restricted to outside of the nucleus in the majority of ESFT, and analysis of HES1 gene targets indicated HES1 to be transcriptionally inactive. Neither forced activation nor pharmacological or genetic blocking of Notch affected HES1 expression in ESFT cells, indicating HES1 expression to be uncoupled from the Notch pathway. Additional functional studies in ESFT cell lines confirmed Notch to be switched off. Finally, unlike experiments in which HES1 expression was modulated, experimental activation of Notch in ESFT cell lines via several means blocked cell proliferation and reduced their clonogenic potential in soft agar. These indicate that HES1 is uncoupled from Notch in ESFT, that EWS–FLI1‐mediated inhibition of Notch contributes to ESFT aggressive cell growth, and support a role for Notch in ESFT tumour suppression, at least partly through the Notch effector HEY1. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Biophysical stimulation with pulsed electromagnetic fields (PEMFs), used in clinics to promote bone repair, favour osteogenic differentiation in human mesenchymal stem cells (hMSCs), however their molecular mechanisms are not clarified. Notch is a pathway regulating cell fate decisions which play a role in skeletal development. Notch signaling is initiated by binding a Notch ligand to a cell surface Notch receptor, resulting in a cleavage of receptor and releasing Notch intracellular domain which translocates to the nucleus and activates transcription of nuclear Notch target genes, such as the Hes/Hey family.The aim of this study is to establish if the known PEMF-induced osteogenic effects may occur through the modulation of Notch pathway. Bone marrow hMSCs cultured in basal condition (control) and in osteoinductive medium (OM) for 28 days were unexposed or continuously exposed to PEMFs (75 Hz, 1.5 mT) (Igea, Carpi, Italy). To block Notch pathway, the Notch inhibitor DAPT was used to treat a series of hMSCs cultured in OM. At different time points (day 1,3,7,14,21,28), osteogenic markers (alkaline phosphatase activity, osteocalcin and matrix mineralization), mRNA expression of osteogenic transcription factors (Runx2, Dlx5, Osterix) as well as of Notch receptors (Notch1-4), their ligands (Jagged1, Dll1 and Dll4) and nuclear target genes (Hey1, Hey2, Hes1, Hes5) were analysed.Our results showed that osteogenic markers and transcription factors increased in OM compared to control and they were further stimulated by PEMFs. Notably, PEMFs significantly increased the expression of Notch4, Dll4, Hey1, Hes1 and Hes5 in the middle phase of differentiation in OM compared to control. In the presence of DAPT, osteogenic markers as well Hes1 and Hes5 expression were significantly inhibited, in unexposed and PEMF-exposed hMSCs. Hey1 was not inhibited by DAPT suggesting a possible regulation by other signaling pathway.These new findings show that PEMFs favor osteogenic differentiation acting through Notch pathway, adding important knowledge concerning the molecular mechanisms by which PEMFs can modulate osteogenesis. This work was supported by grants from IGEA, Carpi, Italy.
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