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Protective effect of propofol on hydrogen peroxide-induced human esophageal carcinoma via blocking the Wnt/?-catenin signaling pathway.

ABSTRACT: Objectives:To analyze the potential influences of propofol on the oxidative stress of H2O2-induced human esophageal squamous cell carcinoma (ESCC) Eca109 cell through mediating the Wnt/?-catenin signaling pathway. Materials and Methods:Eca109 cells were classified into 5 groups: Control group, H2O2 group, Propofol + H2O2 group, Dkk1 (Dickkopf-1, Wnt/?-catenin pathway antagonist) + H2O2 group, and Propofol + LiCl (Lithium chloride, Wnt/?-catenin pathway agonist) + H2O2 group. Western blotting was performed to determine the protein expressions, flow cytometry to measure the content of ROS, immunofluorescence staining to detect the oxidative DNA damage, as well as MTT, AnnexinV-FITC/PI, Wound-healing, and Transwell assays to test the biological characteristics of Eca109 cells. Results:H2O2 resulted in the increased nuclear and cytoplasmatic expression of ?-catenin, reduced p-GSK3? expression, up-regulated ROS content, and induced oxidative DNA damage in Eca109 cells. Moreover, Eca109 cells treated with H2O2 alone had enhanced cell proliferation and metastasis but decreased cell apoptosis, as compared with those without any treatment; meanwhile, the declined Cyt C, Bax, and cleaved caspase-3, as well as the elevated Bcl-2 were also observed in Eca109 cells in the H2O2 group, which were reversed by Propofol or Dkk1. Moreover, Propofol could inhibit the effect of LiCl on activating the Wnt/?-catenin signaling pathway in H2O2-induced Eca109 cells. Conclusion:Propofol elicits protective effects to inhibit H2O2-induced proliferation and metastasis and promote apoptosis of Eca109 cells via blocking the Wnt/?-catenin pathway, offering a possible therapeutic modality for ESCC.

SUBMITTER: Xue JJ

PROVIDER: S-EPMC6312680 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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Protective effect of propofol on hydrogen peroxide-induced human esophageal carcinoma via blocking the Wnt/β-catenin signaling pathway.

Xue Jian-Jun JJ Zhang Ling-Yun LY Hou Huai-Jing HJ Li Yan Y Liang Wan-Sheng WS Yang Ke-Hu KH

Iranian journal of basic medical sciences 20181201 12

<h4>Objectives</h4>To analyze the potential influences of propofol on the oxidative stress of H<sub>2</sub>O<sub>2</sub>-induced human esophageal squamous cell carcinoma (ESCC) Eca109 cell through mediating the Wnt/β-catenin signaling pathway.<h4>Materials and methods</h4>Eca109 cells were classified into 5 groups: Control group, H<sub>2</sub>O<sub>2</sub> group, Propofol + H<sub>2</sub>O<sub>2</sub> group, Dkk1 (Dickkopf-1, Wnt/β-catenin pathway antagonist) + H<sub>2</sub>O<sub>2</sub> group, a ...[more]

PMID: 30627375

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Project description:Oxidants and canonical Wnt/?-catenin signaling have been shown to decrease cardiac Na(+) channel activity by suppressing NaV1.5 expression. Our aims are to determine if hydrogen peroxide (H2O2), one oxidant of reactive oxygen species (ROS), activates Wnt/?-catenin signaling and promotes ?-catenin nuclear activity, leading to suppression of NaV1.5 expression and if this suppression requires the interaction of ?-catenin with its nuclear partner, TCF4 (also called TCF7L2) to decrease SCN5a promoter activity. The results demonstrated that H2O2 increased ?-catenin, but not TCF4 nuclear localization determined by immunofluorescence without affecting total ?-catenin protein level. Furthermore, H2O2 exerted a dose- and time-dependent suppressive effect on NaV1.5 expression. RT-PCR and/or Western blot analyses revealed that overexpressing active form of ?-catenin or stabilizing ?-catenin by GSK-3? inhibitors, LiCl and Bio, suppressed NaV1.5 expression in HL-1 cells. In contrast, destabilization of ?-catenin by a constitutively active GSK-3? mutant (S9A) upregulated NaV1.5 expression. Whole-cell recording showed that LiCl significantly inhibited Na(+) channel activity in these cells. Using immunoprecipitation (IP), we showed that ?-catenin interacted with TCF4 indicating that ?-catenin as a co-transfactor, regulates NaV1.5 expression through TCF4. Analyses of the SCN5a promoter sequences among different species by using VISTA tools indicated that SCN5a promoter harbors TCF4 binding sites. Chromatin IP assays demonstrated that both ?-catenin and TCF4 were recruited in the SCN5a promoter, and regulated its activity. Luciferase promoter assays exhibited that ?-catenin inhibited the SCN5a promoter activity at a dose-dependent manner and this inhibition required TCF4. Small interfering (Si) RNA targeting ?-catenin significantly increased SCN5a promoter activity, leading to enhanced NaV1.5 expression. As expected, ?-catenin SiRNA prevents H2O2 suppressive effects on both SCN5a promoter activity and NaV1.5 expression. Our findings indicate that H2O2 inhibits NaV1.5 expression by activating the Wnt/?-catenin signaling and ?-catenin interacts with TCF4 to transcriptionally suppress cardiac NaV1.5 expression.

Project description:Background Ehrlich solid carcinoma (ESC) is characterized by rapid proliferation and a short survival time. Because Ehrlich ascites carcinoma (EAC) resembles human cancer cells, Ehrlich solid and ascetic forms are commonly used to determine the anticancer effects of various compounds. Luteolin is a flavonoid compound found in many dietary sources, including carrots, peppers, celery, olive oil, peppermint, and oregano. Luteolin has potent anti-inflammatory, antidiabetic, antitumor, and antiapoptotic activities. Aims This study aims to investigate the antitumor activity of luteolin against ESC in rats by affecting the Wnt/β-catenin/SMAD4 pathway. Methods We introduced 0.15 ml of Ehrlich cells (2 × 106) ESC into the left hind thighs of rats. After eight days of inoculation, the rats orally received 25 mg/kg of luteolin daily. We stained sections of tumor tissues with Masson's trichrome. We used another part of the tumor tissue to assess gene and protein expression of Wnt, β-catenin, E-cadherin, and SMAD4. Results Treatment of carcinoma rats with luteolin increased the mean survival time and reduced tumor volume and weight. In addition, examination of tumor tissue stained with Masson's trichrome showed loosely to densely packed collagen fibers in between neoplastic cells and scattered papillary expansion of a loose blue band of collagen expression along the covering adipose connective tissue and extending in a fine strand in between muscle fibers, which was ameliorated by treating rats with luteolin. Finally, treating ESC in rats with luteolin overexpressed E-cadherin and downregulated Wnt, β-catenin, and SMAD4. Conclusions We found luteolin has antineoplastic activity against ESC by reducing tumor size and weight while improving the structure of muscle cells. It works by suppressing Wnt, β-catenin, and SMAD4, resulting in decreased tumor cell proliferation and differentiation. Additionally, luteolin overexpresses E-cadherin, leading to reduced tumor cell invasion and metastasis.

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Protective effect of propofol on hydrogen peroxide-induced human esophageal carcinoma via blocking the Wnt/?-catenin signaling pathway.

Publications

Protective effect of propofol on hydrogen peroxide-induced human esophageal carcinoma via blocking the Wnt/β-catenin signaling pathway.

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