N6-Substituted adenosine analogues, a novel class of JAK2 inhibitors, potently block STAT3 signaling in human cancer cells

Liu, Peng; Zhao, Lu; Xu, Ximing; Liu, Feng; Zhang, Wenchao; Zhou, Cheng; Chen, Jing; Pan, Yanlong; Du, Yiqing; Yang, Jinbo; Wang, Qin

doi:10.1016/j.canlet.2014.07.043

Cited by 7 publications

(3 citation statements)

References 29 publications

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“…Following two weeks, all of the mice were sacrificed by breaking of the neck and the stripped subcutaneous sarcorna tumors were subsequently weighed to evaluated the antitumor effect. Tumors treated with 200 mg/kg XN were stored in formaldehyde for immunohistochemistry as described in a previous study ( 25 ).…”

Section: Methodsmentioning

confidence: 99%

Inhibition of breast cancer cell survival by Xanthohumol via modulation of the Notch signaling pathway inï¿½vivo and inï¿½vitro

et al. 2017

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Natural compounds derived from plants have been an important source of numerous clinically useful anticancer agents. Nevertheless, limited studies indicate that xanthohumol (XN), a major prenylated flavonoid in hop plants (Humulus lupulus), may possess anticarcinogenic properties. The purpose of the present study was to clarify the antitumorigenic effects and the underlying mechanism of XN on breast cancer in vivo and in vitro. A 4T1 breast tumor mouse model was used in the present study to investigate XN suppression of tumor growth as detected by tumorigenicity assays in vivo. In addition, in vitro studies revealed that XN significantly decreased cell viability, induced G0/G1 cell cycle arrest and apoptosis in MCF-7 and MDA-MB-231 cells, as confirmed by an MTT assay, flow cytometry and western blot analysis, indicating anticarcinogenic activity of XN against breast cancer. Furthermore, immunohistochemistry was performed to confirm the inactivation of the Notch signaling pathway, Notch 1 and Ki-67, in vivo; consistently, XN caused decreased activation of the Notch signaling pathway and apoptotic regulators B-cell lymphoma-2 (Bcl-2), Bcl-extra large and caspase 3, as determined by western blot analysis in vitro. This study suggests that XN may potentially be useful as a chemopreventive agent during breast hyperplasia and carcinogenesis, acting via the regulation of Notch associated apoptotic regulators in vivo and in vitro.

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Section: Methodsmentioning

confidence: 99%

Inhibition of breast cancer cell survival by Xanthohumol via modulation of the Notch signaling pathway inï¿½vivo and inï¿½vitro

et al. 2017

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“…STAT3, a critical downstream target of JAK2, participates in JAK2-regulated physiological processes in many cells and tissues [ 15 ]. We thus examined whether STAT3 acts as the downstream effector in miR-375-regulated angiogenesis.…”

Section: Resultsmentioning

confidence: 99%

MiR-375 mitigates retinal angiogenesis by depressing the JAK2/STAT3 pathway

Gong

Han

Zhuang

et al. 2022

Aging

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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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“…Western blotting analysis was performed as described in our previous studies 17 , 18 . Briefly, cells were washed with pre-cold PBS and lysed in RIPA lysis buffer containing 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1% NP-40, 0.5% DOC, 0.1% SDS, 5 mM EDTA, 1 mM EGTA, 20 mM NaF, 2 mM sodium orthovanadate and Protease Inhibitor Cocktail (Roche).…”

Section: Methodsmentioning

confidence: 99%

In vitro and in vivo anticancer activity of Lycorine in prostate cancer by inhibiting NF-κB signaling pathway

Liu¹,

Sun²,

Zhou³

et al. 2022

J. Cancer

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NF-κB transcription factors critically regulate the expression of genes which are involved in important cellular processes, including cellular proliferation and apoptosis. Abnormal activation of the NF-κB signaling pathway has been implicated in a variety of human cancers. Hyper-activation of the NF-κB signaling pathway has been found to lead to tumor survival, anti-apoptosis and invasion in the development of prostate cancer. In the present work, we identified Lycorine as a potent NF-κB inhibitor using a NF-κB activity dependent luciferase reporter in PC3 and DU145 prostate cancer cells. With this reporter gene assay, we found that Lycorine significantly suppressed the constitutive NF-κB activity as well as the NF-κB activity induced by TNF-α, LPS, PMA and IL-1β. Western blotting analysis of the NF-κB signaling pathway further showed that Lycorine inhibited IκB-α (inhibitor of κB) phosphorylation, IκB-α degradation, and p65 phosphorylation. Consistent with this, the subsequent nuclear translocation of p65 was blocked by Lycorine as evidenced in the immunofluorescence assay and western blotting. Furthermore, we observed that cell cycle was arrested at G2/M in Lycorine treated cells using FACS analysis. Western blotting analysis indicated that Lycorine increased the expression of Cyclin D1 but decreased the expression of p21. In addition, FACS analysis showed that Lycorine induced apoptosis in DU145 and PC3 cells. Western blotting analysis revealed that Lycorine decreased the expression of anti-apoptosis genes myc, survivin and Bcl-2 while increased cleavage of PARP. Finally, we observed a significant anticancer effect of Lycorine in a RM-1 prostate cancer xenograft mouse model. In agreement with its in vitro anticancer effect, Lycorine inhibited p65 phosphorylation, IKK-β phosphorylation and the expression of Ki-67, while increased the cleavage of Caspase 3 in tumor tissue. Taken together, our data demonstrated the in vitro and in vivo anti-prostate cancer activity of Lycorine by inhibiting the NF-κB signaling pathway, and highlighted it as a lead compound for further development into an effective anticancer drug.

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N6-Substituted adenosine analogues, a novel class of JAK2 inhibitors, potently block STAT3 signaling in human cancer cells

Cited by 7 publications

References 29 publications

Inhibition of breast cancer cell survival by Xanthohumol via modulation of the Notch signaling pathway inï¿½vivo and inï¿½vitro

Inhibition of breast cancer cell survival by Xanthohumol via modulation of the Notch signaling pathway inï¿½vivo and inï¿½vitro

MiR-375 mitigates retinal angiogenesis by depressing the JAK2/STAT3 pathway

In vitro and in vivo anticancer activity of Lycorine in prostate cancer by inhibiting NF-κB signaling pathway

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