JAC1 Targets YY1-Mediated JWA/p38 MAPK Signaling to Inhibit Proliferation and Induce Apoptosis in TNBC

Abstract Background:Triple negative breast cancer (TNBC)is a type of breast cancer with poor prognosis, and still has no adequate therapeutic target and ideal medicine.The public database and the relative studies have shown that low expression of JWA is closely related to the poor overall survival in many cancers including breast cancer. However, the precise biological functions and behind mechanisms of JWA in TNBC are still unclear.Methods:Both TCGA and GEO databases were used to confirm the relationship between expression levels of JWA and overall survival inTNBC cases.JAC1, an agonisticsmall compound of JWA gene, was used in TNBC modelsin vitro and in vivo. The routine cellular and molecular assays include CCK-8, colony formation, EdUincorporation, the flow cytometry, Western blot, immunohistochemistry,immune-fluorescence microscopy and reporter gene assays were conducted in this study.Results:Low expression of JWA was associated with poor prognosis in TNBC patients. JAC1 treatment inhibited TNBCcells proliferation and promoted apoptosis in vitro and in vivo. JAC1 specifically combined and targeted YY1toeliminate its transcriptional inhibition on JWA gene.At the same time, JAC1promoted ubiquitination and degradation of YY1. The rescued JWA induced G1 phase arrest and apoptosis in TNBC cellsthrough the p38 MAPK signaling pathway. In addition, JAC1 disrupted the interaction between YY1 and HSF1, and suppressed the oncogenic role of HSF1 in TNBC throughp-Aktsignaling pathway.Conclusions:We discovered for the first time that JAC1 is a YY1 targeting compoundand maybe a potential therapeutic agent for TNBC.

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JAC1 Targets YY1-Mediated JWA/p38 MAPK Signaling To Inhibit Proliferation and Induce Apoptosis In TNBC

10.21203/rs.3.rs-1170583/v1 ◽

2021 ◽

Author(s):

Zurong Zhai ◽

Yanlin Ren ◽

Chuanjun Shu ◽

Dongyin Chen ◽

Xia Liu ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Signaling Pathway ◽

P38 Mapk ◽

Poor Prognosis ◽

Mapk Signaling ◽

Poor Overall Survival ◽

Low Expression

Abstract Background: Triple negative breast cancer (TNBC) is a type of breast cancer with poor prognosis, and still has no adequate therapeutic target and ideal medicine. The public database and the relative studies have shown that low expression of JWA is closely related to the poor overall survival in many cancers including breast cancer. However, the precise biological functions and behind mechanisms of JWA in TNBC are still unclear.Methods: Both TCGA and GEO databases were used to confirm the relationship between expression levels of JWA and overall survival in TNBC cases. JAC1, an agonistic small compound of JWA gene, was used in TNBC models in vitro and in vivo. The routine cellular and molecular assays include CCK-8, colony formation, EdU incorporation, the flow cytometry, Western blot, immunohistochemistry, immune-fluorescence microscopy and reporter gene assays were conducted in this study.Results: Low expression of JWA was associated with poor prognosis in TNBC patients. JAC1 treatment inhibited TNBC cells proliferation and promoted apoptosis in vitro and in vivo. JAC1 specifically combined and targeted YY1 to eliminate its transcriptional inhibition on JWA gene. At the same time, JAC1 promoted ubiquitination and degradation of YY1. The rescued JWA induced G1 phase arrest and apoptosis in TNBC cells through the p38 MAPK signaling pathway. In addition, JAC1 disrupted the interaction between YY1 and HSF1, and suppressed the oncogenic role of HSF1 in TNBC through p-Akt signaling pathway.Conclusions: We discovered for the first time that JAC1 is a YY1 targeting compound and maybe a potential therapeutic agent for TNBC.

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Timosaponin AIII Induces G2/M Arrest and Apoptosis in Breast Cancer by Activating the ATM/Chk2 and p38 MAPK Signaling Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2020.601468 ◽

2021 ◽

Vol 11 ◽

Author(s):

Minjie Zhang ◽

Jiaxi Qu ◽

Zhiwei Gao ◽

Qi Qi ◽

Hong Yin ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

P38 Mapk ◽

Mapk Signaling ◽

Mapk Pathways ◽

Phase Arrest ◽

M Phase ◽

Timosaponin Aiii

Timosaponin AIII (TAIII), a steroidal saponin, exerts potent anti-tumor activity in various cancers, especially breast cancer. However, the concrete molecular mechanisms of TAIII against breast cancer are still unclear. Here, we find that TAIII triggers DNA damage, leads to G2/M arrest, and ultimately induces apoptosis in breast cancer both in vitro and in vivo. TAIII induced G2/M phase arrest and apoptosis in MDA-MB-231 and MCF7 cells accompanied with down-regulation of CyclinB1, Cdc2 and Cdc25C. Further data showed that the ATM/Chk2 and p38 pathways were activated representing by up-regulated levels of p-H2A.X and p-p38, which indicated an induction of DNA damage by TAIII, leading to cell cycle arrest and apoptosis. The effects of TAIII were further confirmed by employing inhibitors of ATM and p38 pathways. In vivo, TAIII suppressed the growth of subcutaneous xenograft tumor without obvious toxicity, which indicated by Ki67 and TUNEL analysis. Data also showed that TAIII stimulated the ATM/Chk2 and p38 MAPK pathways in vivo, which in consistent with the effects in vitro. Hence, our data demonstrate that TAIII triggers DNA damage and activates ATM/Chk2 and p38 MAPK pathways, and then induces G2/M phase arrest and apoptosis in breast cancer, which provide theoretical evidence for TAIII utilized as drug against breast cancer.

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Targeting PKM2 promotes chemosensitivity of breast cancer cells in vitro and in vivo

Cancer Biomarkers ◽

10.3233/cbm-210111 ◽

2021 ◽

pp. 1-10

Author(s):

Yu Wang ◽

Han Zhao ◽

Ping Zhao ◽

Xingang Wang

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Cancer Cells ◽

Cancer Patients ◽

Poor Prognosis ◽

Breast Cancer Cells ◽

Breast Cancer Patients ◽

Cancer Tissues

BACKGROUND: Pyruvate kinase M2 (PKM2) was overexpressed in many cancers, and high PKM2 expression was related with poor prognosis and chemoresistance. OBJECTIVE: We investigated the expression of PKM2 in breast cancer and analyzed the relation of PKM2 expression with chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated whether PKM2 could reverse chemoresistance in breast cancer cells in vitro and in vivo. METHODS: Immunohistochemistry (IHC) was performed in 130 surgical resected breast cancer tissues. 78 core needle biopsies were collected from breast cancer patients before neoadjuvant chemotherapy. The relation of PKM2 expression and multi-drug resistance to NAC was compared. The effect of PKM2 silencing or overexpression on Doxorubicin (DOX) sensitivity in the MCF-7 cells in vitro and in vivo was compared. RESULTS: PKM2 was intensively expressed in breast cancer tissues compared to adjacent normal tissues. In addition, high expression of PKM2 was associated with poor prognosis in breast cancer patients. The NAC patients with high PKM2 expression had short survival. PKM2 was an independent prognostic predictor for surgical resected breast cancer and NAC patients. High PKM2 expression was correlated with neoadjuvant treatment resistance. High PKM2 expression significantly distinguished chemoresistant patients from chemosensitive patients. In vitro and in vivo knockdown of PKM2 expression decreases the resistance to DOX in breast cancer cells in vitro and tumors in vivo. CONCLUSION: PKM2 expression was associated with chemoresistance of breast cancers, and could be used to predict the chemosensitivity. Furthermore, targeting PKM2 could reverse chemoresistance, which provides an effective treatment methods for patients with breast cancer.

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Proline-rich protein 11 overexpression is associated with a more aggressive phenotype and poor overall survival in ovarian cancer patients

10.21203/rs.3.rs-35747/v2 ◽

2020 ◽

Author(s):

yu zhan ◽

xueyuan wu ◽

gang zheng ◽

jingjing jin ◽

chaofu li ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Curative Surgery ◽

Poor Overall Survival ◽

Expression Levels ◽

Prognostic Assessment ◽

Therapy Strategies ◽

Proline Rich Protein

Abstract Background: The proline-rich protein 11 (PRR11) is a newly identified oncogene associated with a poor prognosis in several human cancers. Nonetheless, research on its role in ovarian cancer (OC) remains largely understudied. Therefore, this study aims to evaluate the expression levels of PRR11 protein and its role in human ovarian cancer. Methods: Immunohistochemistry analysis was used to evaluate the expression levels of PRR11 protein in human samples obtained from 49 patients diagnosed with OC and subjected to curative surgery in the First Affiliated Hospital of Wenzhou Medical University between 2007 and 2015. Results: In total, 57.1% of the primary OC tumor tissue evaluated demonstrated overexpression of PRR11. Meanwhile, survival analysis showed that the overall survival (OS) of patients presenting overexpression of PRR11 was significantly lower than the OS of the patients with negative PRR11. In subsequent experiments, it was found that silencing the expression of PRR11 expression inhibited the proliferation of tumor cells and the migration of cells in vitro. Further, cells subjected to PRR11 knockdown exhibited a decrease in tumor growth in vivo. The downregulation of PRR11 was coupled with a decrease in N-cadherin and downregulation in the expression of early growth response protein 1 (EGR1).Conclusions: The findings suggest that PRR11 might be considered as a potential target for prognostic assessment and gene therapy strategies for patients diagnosed with OC.

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Proline-rich protein 11 overexpression is associated with a more aggressive phenotype and poor overall survival in ovarian cancer patients

10.21203/rs.3.rs-35747/v3 ◽

2020 ◽

Author(s):

yu zhan ◽

xueyuan wu ◽

gang zheng ◽

jingjing jin ◽

chaofu li ◽

...

Keyword(s):

Ovarian Cancer ◽

Overall Survival ◽

Curative Surgery ◽

Poor Overall Survival ◽

Expression Levels ◽

Prognostic Assessment ◽

Therapy Strategies ◽

Proline Rich Protein

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An Integration of Network Pharmacology and Experimental Verification to Investigate the Mechanism of Guizhi to Treat Nephrotic Syndrome

Frontiers in Pharmacology ◽

10.3389/fphar.2021.755421 ◽

2021 ◽

Vol 12 ◽

Author(s):

Dan He ◽

Qiang Li ◽

Guangli Du ◽

Guofeng Meng ◽

Jijia Sun ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Molecular Docking ◽

Protein Expression ◽

Signaling Pathway ◽

P38 Mapk ◽

Experimental Verification ◽

Active Component ◽

Mapk Signaling

Background: Guizhi has the pharmacological activity of anti-inflammatory. However, the effect mechanism of Guizhi against nephrotic syndrome (NS) remains unclear. A network pharmacological approach with experimental verification in vitro and in vivo was performed to investigate the potential mechanisms of Guizhi to treat NS.Methods: Active compounds and potential targets of Guizhi, as well as the related targets of NS were obtained from the public databases. The intersecting targets of Guizhi and NS were obtained through Venny 2.1.0. The key targets and signaling pathways were determined by protein-protein interaction (PPI), genes ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis. And the overall network was constructed with Cytoscape. Molecular docking verification was carried out by AutoDock Vina. Finally, in vitro and in vivo experiments were performed to verify the mechanism of Guizhi to treat NS.Results: 63 intersecting targets were obtained, and the top five key targets mainly involed in NF- Kappa B and MAPK signaling pathway. In the overall network, cinnamaldehyde (CA) was the top one active compound with the highest degree value. The molecular docking showed that the top five key targets were of good binding activity with the active components of Guizhi. To in vitro experiment, CA, the main active component of Guizhi, inhibited the secretion of IL-1β, IL-6, TNF-α in LPS challenged RAW264.7 cells, and down regulated the protein expression of p-NF-κB p65 and p-p38 MAPK in LPS challenged RAW264.7 cells. In vitro experiment showed that, 24 urinary protein and renal function were increased in ADR group. To western blot, CA down regulated the protein expression of p-p38 MAPK in rats of adriamycin-induced nephropathy.Conclusion: CA might be the main active component of Guizhi to treat NS, and the underlying mechanism might mainly be achieved by inhibiting MAPK signaling pathway.

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Anti-Breast Cancer Effect of 2-Dodecyl-6-Methoxycyclohexa-2,5-Diene-1,4-Dione in vivo and in vitro Through MAPK Signaling Pathway

Drug Design Development and Therapy ◽

10.2147/dddt.s237699 ◽

2020 ◽

Vol Volume 14 ◽

pp. 2667-2684 ◽

Cited By ~ 1

Author(s):

Xing Zhou ◽

Xingchun Wu ◽

Luhui Qin ◽

Shunyu Lu ◽

Hongliang Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Signaling Pathway ◽

Mapk Signaling ◽

Mapk Signaling Pathway

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FOXE1 represses cell proliferation and Warburg effect by inhibiting HK2 in colorectal cancer

Cell Communication and Signaling ◽

10.1186/s12964-019-0502-8 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 6

Author(s):

Weixing Dai ◽

Xianke Meng ◽

Shaobo Mo ◽

Wenqiang Xiang ◽

Ye Xu ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Poor Prognosis ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Glucose Consumption ◽

Underlying Mechanism ◽

Low Expression

Abstract Background Low expression of FOXE1, a member of Forkhead box (FOX) transcription factor family that plays vital roles in cancers, contributes to poor prognosis of colorectal cancer (CRC) patients. However, the underlying mechanism remains unclear. Materials and methods The effects of FOXE1 on the growth of colon cancer cells and the expression of glycolytic enzymes were investigated in vitro and in vivo. Molecular biological experiments were used to reveal the underlying mechanisms of altered aerobic glycolysis. CRC tissue specimens were used to determine the clinical association of ectopic metabolism caused by dysregulated FOXE1. Results FOXE1 is highly expressed in normal colon tissues compared with cancer tissues and low expression of FOXE1 is significantly associated with poor prognosis of CRC patients. Silencing FOXE1 in CRC cell lines dramatically enhanced cell proliferation and colony formation and promoted glucose consumption and lactate production, while enforced expression of FOXE1 manifested the opposite effects. Mechanistically, FOXE1 bound directly to the promoter region of HK2 and negatively regulated its transcription. Furthermore, the expression of FOXE1 in CRC tissues was negatively correlated with that of HK2. Conclusion FOXE1 functions as a critical tumor suppressor in regulating tumor growth and glycolysis via suppressing HK2 in CRC.

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The protective role of microRNA-21 against coxsackievirus B3 infection through targeting the MAP2K3/P38 MAPK signaling pathway

Journal of Translational Medicine ◽

10.1186/s12967-019-2077-y ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 6

Author(s):

Feng He ◽

Zonghui Xiao ◽

Hailan Yao ◽

Sen Li ◽

Miao Feng ◽

...

Keyword(s):

P38 Mapk ◽

Cell Apoptosis ◽

Specific Inhibitor ◽

Inhibitory Effect ◽

Mapk Signaling ◽

Apoptosis Rate ◽

Cvb3 Infection ◽

Interfering Rna

Abstract Background The P38 mitogen-activated protein kinase (MAPK) pathway plays an essential role in CVB3-induced diseases. We previously demonstrated microRNA-21 has potential inhibitory effect on the MAP2K3 which locates upstream of P38 MAPK and was upregulated in mouse hearts upon CVB3 infection. However, the effect and underlying mechanism of miRNA-21 on CVB3 infection remain unclear. Methods We detected continuous changes of cellular miRNA-21 and P38 MAPK proteins expression profiling post CVB3 infection in vitro within 12 h. P38 MAPK signaling was inhibited by the specific inhibitor, small interfering RNA and miRNA-21 mimic in vitro, CVB3 replication, cell apoptosis rate and proliferation were detected. Viral load in the mice heart, cardiomyocyte apoptosis rate and histological of the heart were also detected in the mice model of viral myocarditis pretreated with miRNA-21-lentivirus. Results We observed significant upregulation of miRNA-21 expression followed by suppression of the MAP2K3/P38 MAPK signaling in CVB3-infected Hela cells. The inactivation of the MAP2K3/P38 MAPK signaling by P38 MAPK specific inhibitor, small interfering RNA against MAP2K3, or miRNA-21 overexpression significantly inhibited viral progeny release from CVB3-infected cells. Mechanistically, when compared with control miRNA, miRNA-21 showed no effect on capsid protein VP1 expression and viral load within host cells, while significantly reversing CVB3-induced caspase-3 activation and cell apoptosis rate, further promoting proliferation of infected cells, which indicates the inhibitory effect of miRNA-21 on CVB3 progeny release. In the in vivo study, when compared with control miRNA, miRNA-21 pretreatment remarkably inactivated the MAP2K3/P38 MAPK signaling in mice and protected them against CVB3 infection as evidenced by significantly alleviated cell apoptosis rate, reduced viral titers, necrosis in the heart as well as by remarkably prolonged survival time. Conclusions miRNA-21 were reverse correlated with P38 MAPK activation post CVB3 infection, miRNA-21 overexpression significantly inhibited viral progeny release and decreased myocytes apoptosis rate in vitro and in vivo, suggesting that miRNA-21 may serve as a potential therapeutic agent against CVB3 infection through targeting the MAP2K3/P38 MAPK signaling.

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Interfering MSN-NONO complex–activated CREB signaling serves as a therapeutic strategy for triple-negative breast cancer

Science Advances ◽

10.1126/sciadv.aaw9960 ◽

2020 ◽

Vol 6 (8) ◽

pp. eaaw9960 ◽

Cited By ~ 3

Author(s):

Yuanyuan Qin ◽

Weilong Chen ◽

Guojuan Jiang ◽

Lei Zhou ◽

Xiaoli Yang ◽

...

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cancer Cell Proliferation ◽

Poor Overall Survival ◽

Kinase C ◽

Life Threatening

Triple-negative breast cancer (TNBC) is life-threatening because of limited therapies and lack of effective therapeutic targets. Here, we found that moesin (MSN) was significantly overexpressed in TNBC compared with other subtypes of breast cancer and was positively correlated with poor overall survival. However, little is known about the regulatory mechanisms of MSN in TNBC. We found that MSN significantly stimulated breast cancer cell proliferation and invasion in vitro and tumor growth in vivo, requiring the phosphorylation of MSN and a nucleoprotein NONO-assisted nuclear localization of phosphorylated MSN with protein kinase C (PKC) and then the phosphorylation activation of CREB signaling by PKC. Our study also demonstrated that targeting MSN, NONO, or CREB significantly inhibited breast tumor growth in vivo. These results introduce a new understanding of MSN function in breast cancer and provide favorable evidence that MSN or its downstream molecules might serve as new targets for TNBC treatment.

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