scholarly journals A Preclinical Investigation of GBM-N019 as a Potential Inhibitor of Glioblastoma via Exosomal mTOR/CDK6/STAT3 Signaling

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2391
Author(s):  
Alexander T. H. Wu ◽  
Hsu-Shan Huang ◽  
Ya-Ting Wen ◽  
Bashir Lawal ◽  
Ntlotlang Mokgautsi ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Treatment Resistance ◽  
Signaling Networks ◽  
Drug Candidate ◽  
Signal Transducer ◽  
Cyclin Dependent Kinase ◽  
Stat3 Signaling ◽  
Transcription 3

Glioblastoma (GBM) is one of the most aggressive brain malignancies with high incidences of developing treatment resistance, resulting in poor prognoses. Glioma stem cell (GSC)-derived exosomes are important players that contribute to GBM tumorigenesis and aggressive properties. Herein, we investigated the inhibitory roles of GBM-N019, a novel small molecule on the transfer of aggressive and invasive properties through the delivery of oncogene-loaded exosomes from GSCs to naïve and non-GSCs. Our results indicated that GBM-N019 significantly downregulated the expressions of the mammalian target of rapamycin (mTOR), signal transducer and activator of transcription 3 (STAT3), and cyclin-dependent kinase 6 (CDK6) signaling networks with concomitant inhibitory activities against viability, clonogenicity, and migratory abilities of U251 and U87MG cells. Treatments with GBM-N019 halted the exosomal transfer of protein kinase B (Akt), mTOR, p-mTOR, and Ras-related protein RAB27A to the naïve U251 and U87MG cells, and rescued the cells from invasive and stemness properties that were associated with activation of these oncogenes. GBM-N019 also synergized with and enhanced the anti-GBM activities of palbociclib in vitro and in vivo. In conclusion, our results suggested that GBM-N019 possesses good translational relevance as a potential anti-glioblastoma drug candidate worthy of consideration for clinical trials against recurrent glioblastomas.

scholarly journals Helicobacter pylori Cytotoxin-Associated Gene A Activates the Signal Transducer and Activator of Transcription 3 Pathway In vitro and In vivo

2009 ◽  
Vol 69 (2) ◽  
pp. 632-639 ◽  
Author(s):  
Dana M. Bronte-Tinkew ◽  
Mauricio Terebiznik ◽  
Aime Franco ◽  
Michelle Ang ◽  
Diane Ahn ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Signal Transducer ◽  
Cytotoxin Associated Gene A ◽  
Transcription 3

scholarly journals Astaxanthin Ameliorates Lipopolysaccharide-Induced Neuroinflammation, Oxidative Stress and Memory Dysfunction through Inactivation of the Signal Transducer and Activator of Transcription 3 Pathway

Marine Drugs ◽  
2019 ◽  
Vol 17 (2) ◽  
pp. 123 ◽  
Author(s):  
Ji Han ◽  
Yong Lee ◽  
Jun Im ◽  
Young Ham ◽  
Hee Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Binding ◽  
Inflammatory Responses ◽  
Memory Loss ◽  
Signal Transducer ◽  
Mice Model ◽  
Neuroinflammatory Response ◽  
Transcription 3

Astaxanthin (AXT), a xanthophyll carotenoid compound, has potent antioxidant, anti-inflammatory and neuroprotective properties. Neuroinflammation and oxidative stress are significant in the pathogenesis and development of Alzheimer’s disease (AD). Here, we studied whether AXT could alleviate neuroinflammation, oxidative stress and memory loss in lipopolysaccharide (LPS) administered mice model. Additionally, we investigated the anti-oxidant activity and the anti-neuroinflammatory response of AXT in LPS-treated BV-2 microglial cells. The AXT administration ameliorated LPS-induced memory loss. This effect was associated with the reduction of LPS-induced expression of inflammatory proteins, as well as the production of reactive oxygen species (ROS), nitric oxide (NO), cytokines and chemokines both in vivo and in vitro. AXT also reduced LPS-induced β-secretase and Aβ1–42 generation through the down-regulation of amyloidogenic proteins both in vivo and in vitro. Furthermore, AXT suppressed the DNA binding activities of the signal transducer and activator of transcription 3 (STAT3). We found that AXT directly bound to the DNA- binding domain (DBD) and linker domain (LD) domains of STAT3 using docking studies. The oxidative stress and inflammatory responses were not downregulated in BV-2 cells transfected with DBD-null STAT3 and LD-null STAT3. These results indicated AXT inhibits LPS-induced oxidant activity, neuroinflammatory response and amyloidogenesis via the blocking of STAT3 activity through direct binding.

scholarly journals Splicing factor hnRNPA2B1 contributes to tumorigenic potential of breast cancer cells through STAT3 and ERK1/2 signaling pathway

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769431 ◽  
Author(s):  
Ying Hu ◽  
Zihan Sun ◽  
Jinmu Deng ◽  
Baoquan Hu ◽  
Wenting Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Signal Transducer ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Tumorigenic Potential ◽  
Transcription 3

Increasing evidence has indicated that the splicing factor hnRNPA2B1 plays a direct role in cancer development, progression, gene expression, and signal transduction. Previous studies have shown that knocking down hnRNPA2B1 in breast cancer cells induces apoptosis, but the mechanism and other functions of hnRNPA2B1 in breast cancer are unknown. The goal of this study was to investigate the biological function, clinical significance, and mechanism of hnRNPA2B1 in breast cancer. The expression of hnRNPA2B1 in 92 breast cancer and adjacent normal tissue pairs was analyzed by immunohistochemical staining. Stable clones exhibiting knockdown of hnRNPA2B1 via small hairpin RNA expression were generated using RNA interference technology in breast cancer cell lines. The effects of hnRNPA2B1 on cell proliferation were examined by MTT and EdU assay, and cellular apoptosis and the cell cycle were examined by flow cytometry. A nude mouse xenograft model was established to elucidate the function of hnRNPA2B1 in tumorigenesis in vivo. The role of hnRNPA2B1 in signaling pathways was investigated in vitro. Our data revealed that hnRNPA2B1 was overexpressed in breast cancer tissue specimens and cell lines. Knockdown of hnRNPA2B1 reduced breast cancer cell proliferation, induced apoptosis, and prolonged the S phase of the cell cycle in vitro. In addition, hnRNPA2B1 knockdown suppressed subcutaneous tumorigenicity in vivo. On a molecular level, hnRNPA2B1 knockdown decreased signal transducer and activator of transcription 3 and extracellular-signal-regulated kinase 1/2 phosphorylation. We concluded that hnRNPA2B1 promotes the tumorigenic potential of breast cancer cells, MCF-7 and MDA-MB-231, through the extracellular-signal-regulated kinase 1/2 or signal transducer and activator of transcription 3 pathway, which may serve as a target for future therapies.

scholarly journals Functional Potentiation of Leptin-Signal Transducer and Activator of Transcription 3 Signaling by the Androgen Receptor

Endocrinology ◽  
2008 ◽  
Vol 149 (12) ◽  
pp. 6028-6036 ◽  
Author(s):  
WuQiang Fan ◽  
Toshihiko Yanase ◽  
Yoshihiro Nishi ◽  
Seiichi Chiba ◽  
Taijiro Okabe ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Steroid Hormone Receptors ◽  
Signal Transducer ◽  
Male Mice ◽  
Wild Type ◽  
Stat3 Signaling ◽  
Transcription 3 ◽  
Arcuate Neurons

Hypogonadism is associated with increased fat mass and dysregulation of metabolic homeostasis in men. Our previous study revealed that androgen receptor (AR)-null male mice (ARL-/Y) develop late-onset obesity and are leptin-resistant. The present study evaluated how hypothalamic AR contributes to central leptin-signal transducer and activator of transcription 3 (STAT3) signaling. We evaluated leptin action in wild-type and ARL-/Y mice, the anatomic co-relationship between AR and leptin signaling in the hypothalamus, and the effects of AR on leptin-mediated STAT3 transactivation and nuclear translocation. AR deletion in male mice results in a weaker leptin-induced suppression of food intake and body weight drop even before the onset of overt obesity. In wild-type male but not female mice, AR was highly expressed in various hypothalamic nuclei that also expressed the long-form leptin receptor (OBRB) and co-resided with OBRB directly in the arcuate neurons. In vitro, AR significantly enhanced STAT3-mediated transcription of leptin target genes including POMC and SOCS3. This effect relied on the AR N-terminal activation function-1 (AF-1) domain and was specific to AR in that none of the other sex steroid hormone receptors tested showed similar effects. AR enhanced the low concentrations of leptin-induced STAT3 nuclear translocation in vitro, and ARL-/Y mice receiving leptin had impaired STAT3 nuclear localization in the arcuate neurons. These findings indicate that AR in the hypothalamus functions as a regulator of central leptin-OBRB-STAT3 signaling and has a physiological role in energy homeostasis and metabolic regulation in male mice.

scholarly journals Ponatinib Inhibits Multiple Signaling Pathways Involved in STAT3 Signaling and Attenuates Colorectal Tumor Growth

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 526 ◽  
Author(s):  
Fiona Tan ◽  
Tracy Putoczki ◽  
Jieqiong Lou ◽  
Elizabeth Hinde ◽  
Frédéric Hollande ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Therapeutic Strategy ◽  
Acquired Resistance ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Stat3 Signaling ◽  
Multiple Signaling ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) signaling is a major driver of colorectal cancer (CRC) growth, however therapeutics, which can effectively target this pathway, have so far remained elusive. Here, we performed an extensive screen for STAT3 inhibitors among a library of 1167 FDA-approved agents, identifying Ponatinib as a lead candidate. We found that Ponatinib inhibits STAT3 activity driven by EGF/EGFR, IL-6/IL-6R and IL-11/IL-11R, three major ligand/receptor systems involved in CRC development and progression. Ponatinib was able to inhibit CRC migration and tumor growth in vivo. In addition, Ponatinib displayed a greater ability to inhibit STAT3 activity and mediated superior anti-proliferative efficacy compared to five FDA approved SRC and Janus Kinase (JAK) inhibitors. Finally, long-term exposure of CRC cells to Ponatinib, Dasatinib and Bosutinib resulted in acquired resistance to Dasatinib and Bosutinib occurring within six weeks. However, acquired resistance to Ponatinib was observed after long-term exposure of >4 months. Overall, our results identify a novel anti-STAT3 property of Ponatinib and thus, Ponatinib offers a potential therapeutic strategy for CRC.

scholarly journals Interleukin-11 Promotes Migration, But Not Proliferation, of Human Trophoblast Cells, Implying a Role in Placentation

Endocrinology ◽  
2007 ◽  
Vol 148 (11) ◽  
pp. 5566-5572 ◽  
Author(s):  
Premila Paiva ◽  
Lois A. Salamonsen ◽  
Ursula Manuelpillai ◽  
Claire Walker ◽  
Alejandro Tapia ◽  
...  
Keyword(s):  
First Trimester ◽  
Extravillous Trophoblast ◽  
Hybridoma Cells ◽  
Adult Health ◽  
Signal Transducer ◽  
Human Trophoblast ◽  
And Migration ◽  
Transcription 3

Trophoblast growth and invasion of the uterine endometrium are critical events during placentation and are tightly regulated by factors produced within the trophoblast-endometrial microenvironment. Deficiencies in placentation can result in early miscarriage or preeclampsia and intrauterine growth restriction, leading to impaired fetal health. The latter has been linked to major adult health disorders. IL-11 is essential for blastocyst implantation in mice. In humans, IL-11 and its receptor IL-11 receptor α (IL-11Rα) are maximally expressed in the decidua and chorionic villi during early pregnancy; however, the role of IL-11 in trophoblast function is unknown. Therefore, we examined whether IL-11Rα is expressed in human first trimester implantation sites, and whether IL-11 influences proliferation and migration of a human extravillous trophoblast (EVT)-hybridoma cell line and primary EVT cells, used as models for EVT. Immunoreactive IL-11Rα localized to subpopulations of interstitial and endovascular EVT cells in vivo. In EVT cells in vitro, IL-11: 1) stimulated phosphorylation of signal transducer and activator of transcription-3; 2) was without effect on EVT cell proliferation; and 3) stimulated significant migration of EVT-hybridoma cells (no endogenous IL-11), whereas in primary EVT, blocking endogenous IL-11 inhibited EVT migration by 30–40%. These data demonstrate that IL-11 stimulates human EVT migration, but not proliferation, likely via signal transducer and activator of transcription-3, indicating an important role for IL-11 in placentation.

scholarly journals Erythropoietin Attenuates Experimental Contrast-Induced Nephrology: A Role for the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 Signaling Pathway

2021 ◽  
Vol 8 ◽  
Author(s):  
Jia Yang ◽  
Jiaojiao Zhou ◽  
Xin Wang ◽  
Ling Ji ◽  
Siwen Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Janus Kinase ◽  
Cell Counting ◽  
Signal Transducer ◽  
Janus Kinase 2 ◽  
Protein Levels ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Transcription 3

The aim of the present study was to investigate the effect of erythropoietin (EPO) on contrast-induced nephrology (CIN) in vivo and in vitro. Male C57BL/6J mice were divided into four groups: control, CIN (iohexol 6.0 g/kg), EPO (3,000 IU/kg), and CIN+EPO. Hematoxylin and eosin (H&E) staining and biochemical index analyses were performed to evaluate renal injury. The cellular proliferation rate was detected using the Cell Counting Kit-8 (CCK-8) assay. In addition, a terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometric assay were used to assess the apoptosis of tissue and cells, respectively. Renal protein expression associated with apoptosis, pyroptosis, and signaling pathways was determined by Western blot (WB) assays for tissues and cells. The results showed that EPO significantly decreased serum creatinine, blood urea nitrogen, and cystatin C levels and alleviated renal histological changes in vivo. The protein levels of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway components were overexpressed in the EPO treatment group. Furthermore, EPO suppressed the cell apoptosis and pyroptosis; decreased the protein levels of cleaved caspase-3, Bax, gasdermin D (GSDMD), and caspase-1; and enhanced the expression of Bcl-2. In summary, EPO could exert renoprotective effect by activating the JAK2/STAT3 signaling pathway, which may be a novel potential therapy for the treatment of CIN in the clinic.

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