Effects of AG490 and S3I-201 on regulation of the JAK/STAT3 signaling pathway in relation to angiogenesis in TRAIL-resistant prostate cancer cells in vitro

Gurbuz, Venhar; Konac, Ece; Varol, Nuray; Yılmaz, Akın; Gürocak, Serhat; Menevşe, Sevda; Sözen, Sinan

doi:10.3892/ol.2014.1795

Cited by 40 publications

(28 citation statements)

References 52 publications

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“…7E,F). This indicates that STAT3 may self-regulate, consistent with previous observations(54). Thus, in addition to NFκB, activation of STAT3 is critical for inducing DLL4 in PB DCs.…”

Section: Resultssupporting

confidence: 92%

The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation

Meng

Bai

et al. 2016

The Journal of Immunology

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Notch signaling regulates multiple helper CD4+ T cell programs. We have recently demonstrated that dendritic cells (DCs) expressing the Notch ligand DLL4 are critical for eliciting alloreactive T cell responses and induction of graft-versus-host disease (GVHD) in mice. However, the human counterpart of murine DLL4+ DCs has yet to be examined. We report here the identification of human DLL4+ DCs and their critical role in regulating T helper (Th)1 and Th17 differentiation. CD1c+ DCs and plasmacytoid DCs (pDCs) from the peripheral blood of healthy donors did not express DLL4. In contrast, patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) had a 16-fold more DLL4+CD1c+ DCs than healthy donors. Upon activation of toll-like receptor signaling, healthy donor-derived CD1c+ DCs dramatically upregulated DLL4, as did pDCs to a lesser extent. Activated DLL4+DCs were better able to promote Th1 and Th17 differentiation than unstimulated PB DCs. Blocking DLL4 using a neutralizing antibody decreased Notch signaling in T cells stimulated with DLL4+ DCs, and reduced the generation of Th1 and Th17 cells. Both NFκB and STAT3 were crucial for inducing DLL4 in human DCs. Interestingly, STAT3 directly activated DLL4 transcription and inhibiting STAT3 alone was sufficient to reduce DLL4 in activated PB DCs. Thus, DLL4 is a unique functional molecule of human circulating DCs critical for directing Th1 and Th17 differentiation. These findings identify a pathway for therapeutic intervention for inflammatory disorders in humans, such as GVHD after allogeneic HSCT, autoimmunity and tumor immunity.

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“…7E,F). This indicates that STAT3 may self-regulate, consistent with previous observations(54). Thus, in addition to NFκB, activation of STAT3 is critical for inducing DLL4 in PB DCs.…”

Section: Resultssupporting

confidence: 92%

The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation

Meng

Bai

et al. 2016

The Journal of Immunology

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“…In addition, it has been reported that constitutive STAT3 activation contributed to oncogenesis by modulating angiogenesis,30 and our results showed that EP can down-regulate the STAT3 activity. Taken together, it is highly possible that EP may also attenuate tumor angiogenesis, which needs more experimental evidence.…”

Section: Discussionsupporting

confidence: 77%

Ergosterol peroxide inhibits ovarian cancer cell growth through multiple pathways

Tan¹,

Pan²,

Liu³

et al. 2017

OTT

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Ergosterol peroxide (EP), a sterol derived from medicinal mushrooms, has been reported to exert antitumor activity in several tumor types. However, the role of EP toward ovarian cancer cells has not been investigated. In this study, we analyzed the cytotoxicity of EP in various cell lines representing high-grade serous ovarian cancer and low-grade serous ovarian cancer, respectively. Although EP showed no significant inhibition of the viability of normal ovarian surface epithelial cells, it impaired the proliferation and invasion capacities of tumor cells in a dose-dependent manner. We further figured out key modulators involved in its antitumor effects by quantitative reverse transcription polymerase chain reaction, ELISA, and Western blot. The nuclear β-catenin was down-regulated upon EP treatment, subsequently reducing the Cyclin D1 and c-Myc expression levels. Meanwhile, the protein level of protein tyrosine phosphatase SHP2 was up-regulated in EP treated cells, whereas Src kinase activity was inhibited. Both activation of SHP2 phosphatase and inhibition of Src kinase decreased the phosphorylation level of transducer and activator of STAT3 protein, which was implicated in oncogenesis. On the other hand, EP remarkably inhibited the expression and secretion of VEGF-C, implying its involvement in counteracting tumor angiogenesis. Moreover, EP treatment showed comparable cytotoxic effect with β-catenin knock-down or STAT3 inhibition. Taken together, our results demonstrated that EP showed antitumor effects toward ovarian cancer cells through both β-catenin and STAT3 signaling pathways, making it a promising candidate for drug development.

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“…Phosphorylated STAT3 dimerizes and translocates into the nucleus to bind to specific DNA response elements to induce the transcription of downstream genes, such as BCL-xL, MCL1 and c-Myc (32). Targeting STAT3 signaling results in suppression of the proliferation of various cancer cells in vitro and tumorigenicity in vivo (33,34). Therefore, the identification and development of novel drugs targeting deregulated STAT3 activation effectively remains an important scientific and clinical challenge (35,36).…”

Section: Discussionmentioning

confidence: 99%

The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation

Zhou

Chen

et al. 2015

International Journal of Oncology

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Abstract. Currently, drug discovery and development for clinical treatment of prostate cancer has received increased attention, specifically the STAT3 inhibitor. Our previous study reported that the neuroleptic drug pimozide had antitumor activity against hepatocellular carcinoma cells or stem-like cells through suppressing the STAT3 activity. In the present study we demonstrate that pimozide inhibits cell growth and cellular STAT3 activation in prostate cancer cells. Our results showed that pimozide inhibited prostate cancer cell proliferation in a dose-and time-dependent manner by inducing G1 phase cell cycle arrest, downregulated the ability of colony formation and sphere forming, as well as suppressed cells migration in both DU145 and LNCaP cells. Surprisingly, pimozide reduced the basal expression of phosphorylation STAT3 at tyrosine 705 and reversed the expression of phosphorylation of STAT3 induced by IL-6 addition, suggesting that pimozide can suppress cellular STAT3 activation. Thus, the antipsychotic agent pimozide may be a potential and novel therapeutic for patients with advanced prostate cancer.

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Effects of AG490 and S3I-201 on regulation of the JAK/STAT3 signaling pathway in relation to angiogenesis in TRAIL-resistant prostate cancer cells in vitro

Cited by 40 publications

References 52 publications

The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation

The Notch Ligand DLL4 Defines a Capability of Human Dendritic Cells in Regulating Th1 and Th17 Differentiation

Ergosterol peroxide inhibits ovarian cancer cell growth through multiple pathways

The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation

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