Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK

Jie, Zhiwei; Shen, Shuying; Zhao, Xiangde; Xu, Wenbin; Zhang, Xuyang; Huang, Bao; Tang, Pan; Qin, An; Fan, Shunwu; Xie, Ziang

doi:10.1096/fj.201801977r

Cited by 23 publications

(18 citation statements)

References 45 publications

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“…While the effects of β-catenin agonist SKL2001 and inhibitor XAV939 have been extensively studied in cancers, tumor cell lines, and osteoclasts (Ohashi et al, 2017 ; Jie et al, 2019 ; Yu et al, 2019 ; Zhao et al, 2019 ), their potential in the treatment of cardiovascular diseases related to endothelial dysfunction is unclear. (Jean LeBlanc et al, 2019 ) reported that XAV939 aggravated blood-brain barrier breakdown and increased hemorrhagic transformation incidence.…”

Section: Discussionmentioning

confidence: 99%

Laminar Flow Protects Vascular Endothelial Tight Junctions and Barrier Function via Maintaining the Expression of Long Non-coding RNA MALAT1

Yang

Zhang

Zhu

et al. 2020

Front. Bioeng. Biotechnol.

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Atherosclerotic plaque preferentially develops in arterial curvatures and branching regions, where endothelial cells constantly experience disturbed blood flow. By contrast, the straight arteries are generally protected from plaque formation due to exposure of endothelial cells to vaso-protective laminar blood flow. However, the role of flow patterns on endothelial barrier function remains largely unclear. This study aimed to investigate new mechanisms underlying the blood flow pattern-regulated endothelial integrity. Exposure of human endothelial cells to pulsatile shear (PS, mimicking the laminar flow) compared to oscillatory shear (OS, mimicking the disturbed flow) increased the expressions of long non-coding RNA MALAT1 and tight junction proteins ZO1 and Occludin. This increase was abolished by knocking down MALAT1 or Nesprin1 and 2. PS promoted the association between Nesprin1 and SUN2 at the nuclear envelopes, and induced a nuclear translocation of β-catenin, likely through enhancing the interaction between β-catenin and Nesprin1. In the in vivo study, mice were treated via intraperitoneal injection with β-catenin agonist SKL2001 or its inhibitor XAV939, and they were then subjected to Evans blue injection to assess aortic endothelial permeability. The aortas exhibited a reduced wall permeability to Evans blue in SKL2001-treated mice whereas an enhanced permeability in XAV939-treated mice. We concluded that laminar flow promotes nuclear localization of Nesprins, which facilitates the nuclear access of β-catenin to stimulate MALAT1 transcription, resulting in increased expressions of ZO1 and Occludin to protect endothelial barrier function.

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Section: Discussionmentioning

confidence: 99%

Laminar Flow Protects Vascular Endothelial Tight Junctions and Barrier Function via Maintaining the Expression of Long Non-coding RNA MALAT1

Yang

Zhang

Zhu

et al. 2020

Front. Bioeng. Biotechnol.

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“…In the present study, we demonstrated that Sophoridineinduced β-catenin degradation was not depended on ubiquitin-proteasome pathway but depended on ESRRG, which enhances β-catenin degradation in an ubiquitin-proteasome independent manner [21]. Since ESRRG is a downstream signaling protein of MAPK pathways and the activation of MAPKs ERK1/2, p38 and JNK1/2 promote the phosphorylation of β-catenin [32][33][34], Sophoridine may enhance β-catenin degradation via an MAPK/ESRRG pathway.…”

Section: Discussionmentioning

confidence: 54%

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

et al. 2020

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Background: As a natural alkaloid product isolated from Sophora alopecuroides. L, Sophoridine reshapes gastric cancer immune microenvironment via inhibiting chemotaxis and M2 polarization of tumor-associated macrophages (TAMs). However, the exact effects and underlying mechanism of Sophoridine on gastric cancer cells remains poorly known. Methods: The potential anti-tumor effects of Sophoridine on gastric cancer cell lines, including AGS and SGC7901 cells, were detected by CCK-8, EDU and colony forming assay, immunofluorescence, transwell assay, and flow cytometry. Molecular mechanisms of Sophoridine were investigated by siRNA transfection, nuclear/cytoplasmic extraction and western blot. The synergistic effects of Sophoridine with cisplatin on gastric cancer cells were further investigated in in vitro functional studies. Results: Sophoridine exhibited potent tumor-suppressive activities in gastric cancer cells, including inhibition of proliferation, colony formulation, migration and invasion, as well as induction of apoptosis. In addition, we further showed that Sophoridine induced G2/M cell cycle arrest via inhibiting double-stranded DNA breaks repair and enhanced the efficacy of cisplatin in gastric cancer cells. Molecular studies further revealed that Sophoridine promoted β-catenin degradation by enhancing Estrogen-related receptor gamma (ESRRG) expression, but not depended on ubiquitination-proteasome pathway, either TRIM33-mediated (GSK3β-independent) or altered GSK3β activity, and thus exerted potent tumor-suppressive activities. Conclusion: Sophoridine depends on targeting ESRRG/β-catenin pathway to exert tumor-suppressive activities in gastric cancer cells and enhances the anti-tumor effect of cisplatin. Our study provided the promising preclinical anti-tumor evidence for the potential application of Sophoridine against gastric cancer.

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“…Thus there is a p38/ β-catenin/PAX6 axis in the negative regulation of osteoclastogenesis. 30 It is highly likely to exist a similar axis in breast cancer cells between TNFRSF9 and p38 or p38 and PAX6, which could be further investigated in the future.…”

Section: Discussionmentioning

confidence: 96%

TNFRSF9 Suppressed the Progression of Breast Cancer via the p38MAPK/PAX6 Signaling Pathway

Zhu

Liu

Zhou

et al. 2022

Preprint

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Background Worldwide, Breast cancer is the most common cancer in females. Endocrine therapy can effectively treat 85% of breast cancer patients, but 15% of patients could only be treated with chemotherapy and surgery, and the prognosis is much worse. Immunotherapy is the novel treatment for breast cancer that PD-1 and CTLA-4 antibodies have shown evidence of immune modulation in breast cancer drug trials. Methods and Result In this study, we report that TNFRSF9 regulates the cell proliferation, invasion, and apoptosis of breast cancer cells through regulating the phosphorylation of p38, thus further regulate the expression of PAX6. In both breast cancer tissues and cell lines, the levels of TNFRSF9 are significantly decreased, and breast cancer cell development will be promoted with knockdown of TNFRSF9. Moreover, we identify that downregulation of TNFRSF9 can upregulate the phosphorylated p38 (p-p38) and PAX6. We further elucidate that p-p38 is essential for PAX6 expression that p38 phosphorylation inhibitor can reverse the upregulation of PAX6 and suppress cell proliferation, invasion, and promote apoptosis in breast cancer cells. Conclusions In summary, this study proposed a novel TNFRSF9/p38/PAX6 axis that contributes to tumor suppression, which suggests a potential immunotherapy target for breast cancer.

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Activating; ‐catenin/Pax6 axis negatively regulates osteoclastogenesis by selectively inhibiting phosphorylation of p38/MAPK

Cited by 23 publications

References 45 publications

Laminar Flow Protects Vascular Endothelial Tight Junctions and Barrier Function via Maintaining the Expression of Long Non-coding RNA MALAT1

Laminar Flow Protects Vascular Endothelial Tight Junctions and Barrier Function via Maintaining the Expression of Long Non-coding RNA MALAT1

Sophoridine exerts tumor-suppressive activities via promoting ESRRG-mediated β-catenin degradation in gastric cancer

TNFRSF9 Suppressed the Progression of Breast Cancer via the p38MAPK/PAX6 Signaling Pathway

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