The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

Jin, Xin; Mo, Qingqing; Zhang, Yu; Gao, Yue; Wu, Yuan; Li, Jing; Xing, Hao; Ma, Ding; Gao, Qinglei; Chen, Pingbo

doi:10.1080/15384047.2016.1177676

Cited by 45 publications

(34 citation statements)

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“…It has recently been shown that the MAPK pathways are targets for development for therapeutic agents against cervical cancer [44]. Recently, it has been shown that methyl protodioscin (MPD) induces apoptosis by increasing the levels of phosphorylated JNK and p38 pathway [45].…”

Section: Discussionmentioning

confidence: 99%

Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells

Lin

Lee

Chen

et al. 2018

Cell Physiol Biochem

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Background/Aims: Protodioscin (PD) is a steroidal saponin with anti-cancer effects on a number of cancer cells, but the anti-tumor effects and mechanism of action of PD on human cervical cancer cells is unclear. Methods: We determined cell viability using the MTT assay. Cell death, mitochondrial membrane potential (MMP), intracellular reactive oxygen species (ROS) generation, and endoplasmic reticulum (ER) stress were measured on a flow cytometry. Caspase activation, ER stress, and MMP-dependent apoptosis proteins in cervical cancer cells in response to PD were determined by Western blot analysis. The ability of ATF4 binding to ChIP promoter was measured using the ChIP assay. Results: We demonstrated that PD inhibits cell viability, causes a loss of mitochondrial function, and induces apoptosis, as evidenced by up-regulation of caspase-8, -3, -9, -PARP, and Bax activation, and down-regulation of Bcl-2 expression. PD was shown to induce ROS and the ER stress pathway, including GRP78, p-eIF-2α, ATF4, and CHOP. Pre-treatment with NAC, a ROS production inhibitor, significantly reduced ER stress and apoptosis-related proteins induced by PD. Transfection of GRP78/CHOP-siRNA effectively inhibited PD-induced ER stress-dependent apoptosis. Moreover, treatment with PD significantly increased p38 and JNK activation. Co-administration of a JNK inhibitor (SP600125) or p38 inhibitor (SB203580) abolished cell death and ER stress effects during PD treatment. In addition, PD induced the expression of nuclear ATF4 and CHOP, as well as the binding ability of ATF4 to the CHOP promoter. Conclusion: Our results suggest that PD is a promising therapeutic agent for the treatment of human cervical cancer.

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Section: Discussionmentioning

confidence: 99%

Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells

Lin

Lee

Chen

et al. 2018

Cell Physiol Biochem

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“…For thymidine-taxol, cells were synchronized via double-thymidine blockade and released into taxolcontaining medium (0.1 μM). Cell-cycle distributions were analyzed via flow cytometry as previously described [29] .…”

Section: Cell Synchronization and Cell Cycle Assaysmentioning

confidence: 99%

The LIV-1-GRPEL1 axis adjusts cell fate during anti-mitotic agent-damaged mitosis

Chen

Wang

et al. 2019

eBioMedicine

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Background: Understanding how cells respond to mitotic poisons is of great biomedical and clinical significance. However, it remains unknown how cell-death or survival is determined during exposure to anti-mitotic drugs. Methods: The biological effects of SLC39A6 (LIV-1) and GrpE-like 1 (GRPEL1) on mitotic exit and apoptosis were evaluated both in vitro and in vivo using flow cytometry, western blotting, xenografts and timelapse imaging. The interactions between proteins and the ubiquitination of GRPEL1 were assessed by GST pull down, immunoprecipitation and mass spectrometry analysis. The expression of LIV-1 in cancers was assessed by immunohistochemistry. Findings: Overexpression of LIV-1 led to direct apoptosis. Depleted for LIV-1 evade anti-mitotic agentinduced killing through a rapid exit from arrested mitosis. LIV-1 interacts with GRPEL1 and Stabilizes GRPEL1 Protein by Preventing Ubiquitylation of GRPEL1. LIV-1-GRPEL1 axis depletion works to reduce the mitotic arrest by inducing PP2A-B55 α phosphates activity, while inhibit apoptosis by banding AIF and preventing the latter's release into the nucleus. Loss of function in this axis was frequent in multiple types of human epithelial cancer. Interpretation: These data demonstrate that LIV-1-GRPEL1 axis dually regulates mitotic exit as well as apoptosis by interacting with PP2A B55 α and AIF. Its discovery constitutes a conceptual advance for the decisive mechanism of cell fate during damaged mitosis. Fund: National Clinical Research Center for Obstetric and Gynecologic Diseases, the National Natural Science Foundation of China.

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“…MAPK (p38) inhibitor has been demonstrated antitumor effect on cervical, gastric and colon cancer [27][28][29]. Ralimetinib, an oral MAPK (p38) inhibitor, was currently performed first-in-human phase I pharmaceutical clinical trial in advanced cancers [30].…”

Section: Discussionmentioning

confidence: 99%

Cathepsin C Interacts with TNF-α/p38 MAPK Signaling Pathway to Promote Proliferation and Metastasis in Hepatocellular Carcinoma

Zhang

Xiao

2020

Cancer Res Treat

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Although cathepsin C (CTSC) has been reported to maintain malignant biological properties in various cancers, its functions in hepatocellular carcinoma (HCC) remain obscure. We aimed to investigate the potential role of CTSC in HCC. Materials and Methods HCC tissue microarrays (n=122) were employed to analyze the correlation between CTSC expression and clinicopathological characteristics through immunohistochemistry staining. Quantitative real-time polymerase chain reaction, western blot assay, Cell Counting Kit-8 assay, colony formation, cell migration, and invasion assays, xenograft mice model were adopted to validate what had been indicated by the bioinformatic web tools. Results By bioinformatic tools and tissue microarrays, CTSC was found upregulated in HCC compared with normal liver tissues, and its higher expression was correlated with poor prognosis of HCC patients (hazard ratio, 2.402; 95% confidence interval, 1.493 to 3.865; p < 0.001). By gain/loss-of-function assays, we implicated that CTSC functioned as an oncogene to promote the proliferation and metastasis of HCC cells. Mechanistically, we revealed that CTSC was involved in several cancer-related signaling pathways by Gene Set Enrichment Analysis, among which tumor necrosis factor ! (TNF-!)/p38 pathway was verified to be activated by CTSC. Furthermore, we found that TNF-! could activate CTSC expression in a concentration-dependent manner. Ralimetinib, an oral p38 mitogen-activated protein kinase (MAPK) inhibitor could inhibit CTSC expression. These indicated a potential positive feedback loop between CTSC and TNF-!/MAPK (p38) signaling. Conclusion Taken together, CTSC plays an important role in the growth and metastasis of HCC and may be a promising therapeutic target upon HCC.

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The p38 MAPK inhibitor BIRB796 enhances the antitumor effects of VX680 in cervical cancer

Cited by 45 publications

References 58 publications

Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells

Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells

The LIV-1-GRPEL1 axis adjusts cell fate during anti-mitotic agent-damaged mitosis

Cathepsin C Interacts with TNF-α/p38 MAPK Signaling Pathway to Promote Proliferation and Metastasis in Hepatocellular Carcinoma

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