Inhibition of STAT3/VEGF/CDK2 axis signaling is critically involved in the antiangiogenic and apoptotic effects of arsenic herbal mixture PROS in non-small lung cancer cells

Lee, Hyemin; Lee, Hyo‐Jung; Bae, Ill Ju; Kim, Jeong Jin; Kim, Sung‐Hoon

doi:10.18632/oncotarget.21973

Cited by 15 publications

(14 citation statements)

References 55 publications

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“…Thus, the underlying mechanisms, such as whether β-elemene inhibits the upstream molecules of Stat3 resulting affected Stat3-associated signaling, remain inconclusive, and more experiments are still needed to elucidate them. In accordance with this, inactivation and inhibition of Stat3 signaling have been shown to be involved in the inhibition of cell growth and progression in several cancer types, including lung cancer 10 , 51 – 53 . This finding suggested that targeting Stat3 could be used in lung cancer treatment.…”

Section: Discussionsupporting

confidence: 54%

Inactivation of Stat3 and crosstalk of miRNA155-5p and FOXO3a contribute to the induction of IGFBP1 expression by beta-elemene in human lung cancer

et al. 2018

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β-Elemene, an active component of natural plants, has been shown to exhibit anticancer properties. However, the detailed mechanism underlying these effects has yet to be determined. In this study, we show that β-elemene inhibits the growth of lung cancer cells. Mechanistically, we found that β-elemene decreased the phosphorylation of signal transducer and activator of transcription 3 (Stat3) and miRNA155-5p mRNA but induced the protein expression of human forkhead box class O (FOXO)3a; the latter two were abrogated in cells with overexpressed Stat3. Notably, miRNA155-5p mimics reduced FOXO3a luciferase reporter activity in the 3-UTR region and protein expression, whereas overexpressed FOXO3a countered the reduction of the miRNA155-5p levels by β-elemene. Moreover, β-elemene increased the mRNA and protein expression levels as well as promoter activity of insulin-like growth factor-binding protein 1 (IGFBP1); this finding was not observed in cells with a silenced FOXO3a gene and miRNA155-5p mimics. Finally, silencing of IGFBP1 blocked β-elemene-inhibited cell growth. Similar findings were observed in vivo. In summary, our results indicate that β-elemene increases IGFBP1 gene expression via inactivation of Stat3 followed by a reciprocal interaction between miRNA155-5p and FOXO3a. This effect leads to inhibition of human lung cancer cell growth. These findings reveal a novel molecular mechanism underlying the inhibitory effects of β-elemene on lung cancer cells.

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Section: Discussionsupporting

confidence: 54%

Inactivation of Stat3 and crosstalk of miRNA155-5p and FOXO3a contribute to the induction of IGFBP1 expression by beta-elemene in human lung cancer

et al. 2018

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“…Scholars have confirmed that salvianolic acid B can have a role in improving cognition and promoting angiogenesis by activating p-STAT3 to produce VEGF-A (23). Inhibition of the STAT3/VEGF-A pathway in vectors for non-small cell lung cancer would inhibit angiogenesis and promote tumor cell apoptosis (24). Taken together, the evidence suggests that STAT3 is, perhaps, not only downstream of IL-9/IL-9R but also an upstream molecule of VEGF-A.…”

Section: Discussionmentioning

confidence: 99%

Neutralization of interleukin‐9 ameliorates experimental stroke by repairing the blood–brain barrierviadown‐regulation of astrocyte‐derived vascular endothelial growth factor‐A

et al. 2019

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Astrocytes mediate the destruction of the blood–brain barrier (BBB) during ischemic stroke (IS). IL‐9 is a pleiotropic cytokine that we previously found to be highly expressed in peripheral blood mononuclear cells from patients with IS, and the presence of IL‐9 receptors on astrocytes has been reported in the literature. Here, we detected the effect of IL‐9 on astrocytes using an anti–IL‐9‐neutralizing antibody to treat rats with experimental stroke. Supernatants from astrocytes treated with or without oxygen–glucose deprivation and/or IL‐9 were incubated with bEnd.3 cell monolayers after blocking the IL‐9 receptor on the endothelium. Immunofluorescence staining and Western blot analyses were conducted to observe the change in tight junction proteins (TJPs) in bEnd.3 cells as well as the level of VEGF‐A and possible signal pathways in astrocytes. We also applied middle cerebral artery occlusion (MCAO) models to determine the effect of anti–IL‐9‐neutralizing antibodies on IS. As a result, astrocyte‐conditioned medium treated with IL‐9 aggravated the disruption of the BBB accomplished by the degradation of TJPs in endothelial cells. In addition, IL‐9 increased the level of VEGF‐A in astrocytes, and blocking the effect of VEGF‐A reversed the breakdown of the BBB. In the MCAO model, anti–IL‐9‐neutralizing antibody reduced the infarct volume and BBB destruction. Mechanistically, the anti–IL‐9‐neutralizing antibody repaired the damaged TJPs (zonula occludens 1, occludin, and claudin‐5) and induced a decrease in VEGF‐A expression in ischemic lateral brain tissue. In contrast, a local injection of recombinant murine IL‐9 to the brain resulted in a marked up‐regulation of VEGF‐A in the striatum. In conclusion, anti–IL‐9‐neutralizing antibody can reduce the severity of IS partially by alleviating the destruction of the BBB via down‐regulation of astrocyte‐derived VEGF‐A. This finding suggests that targeting IL‐9 or VEGF‐A could provide a new direction for the treatment of IS.—Tan, S., Shan, Y., Lin, Y., Liao, S., Zhang, B., Zeng, Q., Wang, Y., Deng, Z., Chen, C, Hu, X., Peng, L., Qiu, W., Lu, Z. Neutralization of IL‐9 ameliorates experimental stroke by repairing the blood–brain barrier via down‐regulation of astrocyte‐derived vascular endothelial growth factor‐A. FASEB J. 33, 4376–4387 (2019). http://www.fasebj.org

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“…It has been reported that HG promotes the expression of VEGF by activating STAT3 in non-small lung cancer cells [33], suggesting that the effects of GLUT4 on VEGF may also be dependent on STAT3 activation. Of note, our results suggest that the regulation of HG, estrogen and GLUT4 on VEGF may also contribute to the progression of UEC by stimulating angiogenesis.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion

Gu¹,

Xie²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Uterus endometrial cancer (UEC) is the common malignancy among gynecologic cancers, and most of them are type I estrogen-dependent UEC. Diabetes is well-known risk factor for the development of UEC. However, the underlying link between high glucose (HG) and the estrogen receptor in UEC remains unclear. Epithelial-mesenchymal transition (EMT) has also been shown to occur during the initiation of metastasis in cancer progression. The aim of this study was to determine the relationships and roles of HG, estrogen receptor and EMT in the growth and migration of UEC. Methods: The expression of glucose transport protein 4 (GLUT4) in the control endometrium and UEC tissues was detected by immunohistochemistry (IHC); the cell viability and invasion were analyzed through CCK-8 and Matrigel invasion assays; the transcriptional level of EMT-related genes was evaluated through real-time PCR; and the effect of HG and / or GLUT4 on estrogen receptors, vascular endothelial growth factor (VEGF) and its receptor VEGFR was analyzed through western blotting, ELISA and flow cytometry (FCM) assay, respectively. In addition, Ishikawa-xenografted nude mice were constructed and were used to analyze the effect of estrogen and GLUT4 on the growth of UEC in vivo. Results: Here, we found that exposure to HG led to a high level of viability and invasion of UEC cell lines (UECC, Ishikawa and RL95-2 cells). Compared with the normal endometrium, a higher level of GLUT4 was observed in UEC tissues. Silencing GLUT4 obviously inhibited the HG-promoted viability, invasion and expression of EMT-related genes (TWIST, SNAIL and CTNNB1) of UECC promoted by HG. Further analysis showed that HG and GLUT4 promoted the secretion of VEGF and expression of VEGFR in UECC. Treatment with HG led to the increase of estrogen receptor α (ERα) and β (ERβ) in UECC, blocking ERα or ERβ resulted in the decreases in GLUT4 expression, TWIST, SNAIL and CTNNB1 transcription, and VEGF and VEGFR expression in UECC. Treatment with anti-human VEGF neutralizing antibody restricted the viability and invasion of UECC that was induced by HG and estrogen. Exposure to estrogen accelerated growth, VEGF production, and TWIST and CTNNB1 expression in UEC in Ishikawa-xenografted nude mice, and silencing GLUT4 restricted these effects. Conclusion: These data suggest that HG increases GLUT4 and VEGF/VEGFR expression, further promotes EMT process and accelerates the development of UEC by up-regulating ER

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Inhibition of STAT3/VEGF/CDK2 axis signaling is critically involved in the antiangiogenic and apoptotic effects of arsenic herbal mixture PROS in non-small lung cancer cells

Abstract: ABSTRACT

Cited by 15 publications

References 55 publications

Inactivation of Stat3 and crosstalk of miRNA155-5p and FOXO3a contribute to the induction of IGFBP1 expression by beta-elemene in human lung cancer

Inactivation of Stat3 and crosstalk of miRNA155-5p and FOXO3a contribute to the induction of IGFBP1 expression by beta-elemene in human lung cancer

Neutralization of interleukin‐9 ameliorates experimental stroke by repairing the blood–brain barrierviadown‐regulation of astrocyte‐derived vascular endothelial growth factor‐A

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion

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