Puerarin suppresses hypoxia-induced vascular endothelial growth factor upregulation in human retinal pigmented epithelial cells by blocking JAK2/STAT3 pathway.
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ABSTRACT:
SUBMITTER: Tang H
PROVIDER: S-EPMC9275891 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.
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Project description:Colorectal cancer (CRC) is the third most common cancer worldwide and is associated with a poor clinical outcome and survival. Therefore, the development of novel therapeutic agents for CRC is imperative. Atractylenolide I (AT-I) is a sesquiterpenoid lactone derivative of Rhizoma Atractylodis macrocephalae that exhibits diverse biological activities, including anti-cancer activities. However, the effects and potential mechanism of AT-I in CRC have yet to be fully elucidated. In this study, we aimed to examine the anti-cancer properties of AT-I and the associated functional mechanisms in vitro and in vivo. We found that AT-I treatment significantly suppressed the viability of CRC cell lines and inhibited colony formation, but to a lesser extent in NCM460 cells. Annexin V/PI staining showed that AT-I induced apoptosis in CRC cells, accompanied by increased caspase-3 and PARP-1 cleavage, enhanced expression of Bax, and reduced expression of Bcl-2. Furthermore, AT-I blocked cell glycolysis by inhibiting both glucose uptake and lactate production in CRC cells, and specifically downregulated the expression of the rate-limiting glycolytic enzyme HK2. In contrast, it had no discernable effects on the glycolytic enzymes PFK and PKM2. A mechanistic study revealed that AT-1 negatively regulates STAT3 phosphorylation through direct interaction with JAK2, thereby inhibiting its activation. Moreover, restoring the expression of STAT3 reversed the effect of AT-I on apoptosis and glycolysis in CRC cells. In vivo results revealed that AT-I significantly suppressed tumor growth in HCT116-xenografted mice. Collectively, our findings indicate that the anti-cancer activity of AT-I in CRC is associated with the induction of apoptosis and suppression of glycolysis in CRC cells, via the disruption of JAK2/STAT3 signaling. Our preliminary experimental data indicate that AT-I may have applications as a promising candidate for the treatment of CRC.
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Project description:Background Vascular calcification (VC), associated with enhanced cardiovascular morbidity and mortality, is characterized by the osteogenic transdifferentiation of vascular smooth muscle cells. Inflammation promotes VC initiation and progression. Interleukin (IL)-29, a newly discovered member of type III interferon, has recently been implicated in the pathogenesis of autoimmune diseases. Here we evaluated the role of IL-29 in the VC process and underlying inflammatory mechanisms. Methods and Results The mRNA expression of IL-29 was significantly increased and positively associated with an increase in BMP2 (bone morphogenetic protein 2) mRNA level in calcified carotid arteries from patients with coronary artery disease or chronic kidney disease. IL-29 and BMP2 proteins are colocalized in human calcified arteries. IL-29 binding to its specific receptor IL-28Rα (IL-28 receptor α) (IL-29/IL-28Rα) inhibited the proliferation of rat vascular smooth muscle cells without altering cell apoptosis or migration. IL-29 promoted the calcification of rat vascular smooth muscle cells and their osteogenic transdifferentiation in vitro as well as the rat aortic ring calcification ex vivo, induced by the calcification medium or osteogenic medium. The procalcification effect of IL-29 was reduced by pharmacological inhibition of IL-29/IL-28Rα binding as well as suppression of janus kinase 2/signal transducer and activator of transcription pathway activation, accompanied by decreased BMP2 expression in the cultured rat vascular smooth muscle cells. Conclusions These results suggest an important role of IL-29 in VC development, at least partly, via activating the janus kinase 2/signal transducer and activator of transcription 3 signaling. Inhibition of IL-29 or its specific receptor, IL-28Rα, may provide a novel strategy to reduce VC in patients with vascular diseases.
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Project description:Aberrant neovascularization in the retina is an important threat to vision and closely related to several retinal diseases, such as wet form of age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. However, the pathogenesis remains largely unknown. MicroRNAs (miRNAs) have been demonstrated to play critical regulatory roles in angiogenesis. Therefore, we aimed to identify the key miRNAs that regulate retinal neovascularization and elucidate the potential underlying mechanisms. In the present study, we performed RNA sequencing of microRNAs in the retina and found that miR-375 was significantly downregulated in the retina of oxygen-induced retinopathy mice. In retinal microvascular endothelial cells (RMECs), overexpression of miR-375 inhibited cell proliferation and angiogenesis. Conversely, inhibition of miR-375 had the opposite effects. Moreover, our results showed that miR-375 negatively regulated the protein expression of JAK2 by inhibiting its translation. The promoting effects of anti-miR-375 on cell proliferation and angiogenesis were attenuated by an inhibitor of STAT3. These results indicate that miR-375 mitigates cell proliferation and angiogenesis, at least in part, through the JAK2/STAT3 pathway in RMECs, which implies an important underlying mechanism of retinal angiogenesis and provides potential therapeutic targets for retinal microangiopathy.
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Project description:BackgroundAs a commonly mutated form of the epidermal growth factor receptor, EGFRvIII strongly promotes glioblastoma (GBM) tumor invasion and progression, but the mechanisms underlying this promotion are not fully understood.MethodsThrough gene manipulation, we established EGFRvIII-, wild-type EGFR-, and vector-expressing GBM cells. We used cDNA microarrays, bioinformatics analysis, target-blocking migration and invasion assays, Western blotting, and an orthotopic U87MG GBM model to examine the phenotypic shifts and treatment effects of EGFRvIII expression in vitro and in vivo. Confocal imaging, co-immunoprecipitation, and siRNA assays detected the focal adhesion-associated complex and their relationships to the EGFRvIII/JAK2/STAT3 axis in GBM cells.ResultsThe activation of JAK2/STAT3 signaling is vital for promoting migration and invasion in EGFRvIII-GBM cells. AG490 or WP1066, the JAK2/STAT3 inhibitors, specifically destroyed EGFRvIII/JAK2/STAT3-related focal adhesions and depleted the activation of EGFR/Akt/FAK and JAK2/STAT3 signaling, thereby abolishing the ability of EGFRvIII-expressing GBM cells to migrate and invade. Furthermore, the RNAi silencing of JAK2 in EGFRvIII-expressing GBM cells significantly attenuated their ability to migrate and invade; however, as a result of a potential EGFRvIII-JAK2-STAT3 activation loop, neither EGFR nor STAT3 knockdown yielded the same effects. Moreover, AG490 or JAK2 gene knockdown greatly suppressed tumor invasion and progression in the U87MG-EGFRvIII orthotopic models.ConclusionTaken together, our data demonstrate that JAK2/STAT3 signaling is essential for EGFRvIII-driven migration and invasion by promoting focal adhesion and stabilizing the EGFRvIII/JAK2/STAT3 axis. Targeting JAK2/STAT3 therapy, such as AG490, may have potential clinical implications for the tailored treatment of GBM patients bearing EGFRvIII-positive tumors.
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Project description:BackgroundFibroblast-like synoviocytes (FLS) have cancer cell-like characteristics, such as abnormal proliferation and resistance to apoptosis, and play a pathogenic role in rheumatoid arthritis (RA). Hyperproliferation of RA-FLS that can be triggered by the activation of interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling destructs cartilage and bone in RA patients. Chrysoeriol is a flavone found in medicinal herbs such as Chrysanthemi Indici Flos (the dried capitulum of Chrysanthemum indicum L.). These herbs are commonly used in treating RA. Chrysoeriol has been shown to exert anti-inflammatory effects and inhibit STAT3 signaling in our previous studies. This study aimed to determine whether chrysoeriol inhibits hyperproliferation of RA-FLS, and whether inhibiting STAT3 signaling is one of the underlying mechanisms.MethodsIL-6/soluble IL-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS were used to evaluate the effects of chrysoeriol. CCK-8 assay and crystal violet staining were used to examine cell proliferation. Annexin V-FITC/PI double staining was used to detect cell apoptosis. Western blotting was employed to determine protein levels.ResultsChrysoeriol suppressed hyperproliferation of, and evoked apoptosis in, IL-6/sIL-6R-stimulated RA-FLS. The apoptotic effect of chrysoeriol was verified by its ability to cleave caspase-3 and caspase-9. Mechanistic studies revealed that chrysoeriol inhibited activation/phosphorylation of Janus kinase 2 (JAK2, Tyr1007/1008) and STAT3 (Tyr705); decreased STAT3 nuclear level and down-regulated protein levels of Bcl-2 and Mcl-1 that are transcriptionally regulated by STAT3. Over-activation of STAT3 significantly diminished anti-proliferative effects of chrysoeriol in IL-6/sIL-6R-stimulated RA-FLS.ConclusionsWe for the first time demonstrated that chrysoeriol suppresses hyperproliferation of RA-FLS, and suppression of JAK2/STAT3 signaling contributes to the underlying mechanisms. This study provides pharmacological and chemical justifications for the traditional use of chrysoeriol-containing herbs in treating RA, and provides a pharmacological basis for developing chrysoeriol into a novel anti-RA agent.
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Project description:It is known that chronic stress modulates multiple processes in a complex microenvironment, such as angiogenesis and immune function. However, the role of chronic stress inducing tumor angiogenesis and how it contributes to tumor progression are not quite clear. The following study assess psychological state from numerous ambulatory cancer cases (n=332), and chronic stress-related hormone levels were further measured. Here, we show that chronic stress not only causes behavioral changes in human, most importantly attributed to an elevated level of stress-related hormones. To address this, isoprenaline, the agonist of β2-adrenergic receptor (β2-AR), was utilized for simulating chronic stress and demonstrating the mechanism of stress in tumor angiogenesis at molecular level both in vivo and in vitro. As suggested by this study, isoprenaline promote VEGF autocrine of HUVECs, which can induce plexinA1 and VEGFR2 expression. Moreover, we show that isoprenaline promoted the expression of p-JAK2 and p-STAT3 in vitro. The results reveal that, isoprenaline enhances the autocrine of VEGF in HUVECs and up-regulating plexinA1 and VEGFR2 levels, thus activating the phosphorylation of JAK2-STAT3 pathway, the two essential parts during angiogenesis. The present work indicates that, the mechanism of chronic stress in enhancing angiogenesis is probably achieved through activating the plexinA1/VEGFR2-JAK2-STAT3 signal transduction pathway within HUVECs, and this is probably a candidate target for developing a strategy against angiogenesis in cancer.
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Project description:Cerebral ischemia triggers vascular dementia (VD), which is characterized by memory loss, cognitive deficits, and vascular injury in the brain. Puerarin (Pur) represents the major isoflavone glycoside of Radix Puerariae, with verified neuroprotective activity and cardiovascular protective effects. However, whether Pur ameliorates cognitive impairment and vascular injury in rats with permanent occlusion of bilateral common carotid arteries (BCCAO) remains unknown. This work aimed to assess Pur's effects on BCCAO-induced VD and to dissect the underlying mechanisms, especially examining the function of transient receptor potential melastatin-related 2 (TRPM2) in alleviating cognitive deficits and vascular injuries. Rats with BCCAO developed VD. Pur (50, 100, and 150 mg/kg) dose-dependently attenuated the pathological changes, increased synaptic structural plasticity in the dorsal CA1 hippocampal region and decreased oxidative stress, which eventually reduced cognitive impairment and vascular injury in BCCAO rats. Notably, Pur-improved neuronal cell loss, synaptic structural plasticity, and endothelial vasorelaxation function might be mediated by the reactive oxygen species (ROS)-dependent TRPM2/NMDAR pathway, evidenced by decreased levels of ROS, malondialdehyde (MDA), Bax, Bax/Bcl2, and TRPM2, and increased levels of superoxide dismutase (SOD), Bcl2, and NR2A. In conclusion, Pur has therapeutic potential for VD, alleviating neuronal cell apoptosis and vascular injury, which may be related to the ROS-dependent TRPM2/NMDAR pathway.
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Project description:Basal cell carcinoma is driven by the aberrant activation of hedgehog signaling. DEAD (Asp-Glu-Ala-Asp) box protein 5 is frequently overexpressed in human cancer cells and associated with the tumor growth and invasion. The purpose of this study was to investigate the role of DEAD (Asp-Glu-Ala-Asp) box protein 5 in the growth, migration, and invasion of basal cell carcinoma. The role of DEAD (Asp-Glu-Ala-Asp) box protein 5 was detected by quantitative real-time polymerase chain reaction, Western blot, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay in basal cell carcinoma cells. The associations between JAK2/STAT3 pathway and DEAD (Asp-Glu-Ala-Asp) box protein 5 were analyzed in basal cell carcinoma cells. Results showed that DEAD (Asp-Glu-Ala-Asp) box protein 5 is overexpressed in basal cell carcinoma cells. DEAD (Asp-Glu-Ala-Asp) box protein 5 knockdown inhibited the migration and invasion of basal cell carcinoma cells. DEAD (Asp-Glu-Ala-Asp) box protein 5 knockdown increased the apoptosis of basal cell carcinoma cells induced by tunicamycin. Results found that DEAD (Asp-Glu-Ala-Asp) box protein 5 knockdown increased JAK2 and STAT3 expression in basal cell carcinoma cells. JAK2 inhibitor decreased STAT3 expression and abolished the inhibitory effects of DEAD (Asp-Glu-Ala-Asp) box protein 5 silencing on migration and invasion in basal cell carcinoma cells. In conclusion, these results indicate that DEAD (Asp-Glu-Ala-Asp) box protein 5 is a potential target for inhibiting basal cell carcinoma cells growth, migration, and invasion by downregulating JAK2/STAT3 pathway.
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Project description:Long noncoding RNAs (lncRNAs), widely expressed in mammalian cells, play pivotal roles in osteosarcoma (OS) progression. Nevertheless, the detailed molecular mechanisms of lncRNA KIAA0087 in OS remain obscure. Here, the roles of KIAA0087 in OS tumorigenesis were investigated. KIAA0087 and miR-411-3p levels were detected by RT-qPCR. Malignant properties were assessed by CCK-8, colony formation, flow cytometry, wound healing, and transwell assays. SOCS1, EMT, and JAK2/STAT3 pathway-related protein levels were measured by western blotting. Direct binding between miR-411-3p and KIAA0087/SOCS1 was validated by a dual-luciferase reporter, RIP, and FISH assays. In vivo growth and lung metastasis were evaluated in nude mice. The expression levels of SOCS1, Ki-67, E-cadherin, and N-cadherin in tumor tissues were measured by immunohistochemical staining. Downregulation of KIAA0087 and SOCS1 and upregulation of miR-411-3p were found in OS tissues and cells. Low expression of KIAA0087 was associated with a poor survival rate. Forced expression of KIAA0087 or miR-411-3p inhibition repressed the growth, migration, invasion, EMT, and activation of the JAK2/STAT3 pathway and triggered apoptosis of OS cells. However, the opposite results were found with KIAA0087 knockdown or miR-411-3p overexpression. Mechanistic experiments indicated that KIAA0087 enhanced SOCS1 expression to inactivate the JAK2/STAT3 pathway by sponging miR-411-3p. Rescue experiments revealed that the antitumor effects of KIAA0087 overexpression or miR-411-3p suppression were counteracted by miR-411-3p mimics or SOCS1 inhibition, respectively. Finally, in vivo tumor growth and lung metastasis were inhibited in KIAA0087-overexpressing or miR-411-3p-inhibited OS cells. In summary, the downregulation of KIAA0087 promotes the growth, metastasis, and EMT of OS by targeting the miR-411-3p-mediated SOCS1/JAK2/STAT3 pathway.
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