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Antitumor effects of aconitine in A2780 cells via estrogen receptor ??mediated apoptosis, DNA damage and migration.

ABSTRACT: Ovarian cancer (OVCA) is the deadliest type of malignant gynecological disease, and previous studies have demonstrated that estrogen receptor ? (ER?) serves important roles in this disease. Aconitine, a toxin produced by the Aconitum plant, displays potent effects against cancers. The aim of the study was to investigate the pharmacological activities and mechanisms of aconitum on OVCA. In the present study, the activity of aconitine in the human OVCA A2780 cell line was investigated. The results revealed that aconitine suppressed cell viability, colony formation and motility. Terminal deoxynucleotidyl?transferase?mediated dUTP nick end labeling, mitochondria membrane potential and comet assays showed that aconitine induced mitochondria apoptosis and DNA damage in A2780 cells. Investigation of the mechanism revealed that a high expression of ER? and prolyl hydroxylase 2 was detected after aconitine treatment, and aconitine significantly suppressed the expression of vascular endothelial growth factor and hypoxia?inducible factor 1? to activate ER? signaling. Moreover, the expression levels of p53, Bax, apoptotic peptidase activating factor 1, cytochrome C, cleaved caspase?3/9 and cleaved poly (ADP?ribose) polymerase were upregulated, and the expression levels of Bcl?2, Bcl?xl and phosphorylated ATM serine/threonine kinase were downregulated by aconitine. Interestingly, aconitine also markedly downregulated the expression of matrix metalloproteinase 2 (MMP2) and MMP9, which are associated with tumor invasion. In addition, a molecular docking assay revealed that aconitine exerted strong affinity towards ER? mainly through hydrogen bonding and hydrophobic effects. Collectively, these results suggested that aconitine suppressed OVCA cell growth by adjusting ER??mediated apoptosis, DNA damage and migration, which should be considered a potential option for the future treatment of OVCA.

SUBMITTER: Wang X

PROVIDER: S-EPMC7411431 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Antitumor effects of aconitine in A2780 cells via estrogen receptor β‑mediated apoptosis, DNA damage and migration.

Wang Xiuying X Lin Yuanyuan Y Zheng Yi Y

Molecular medicine reports 20200710 3

Ovarian cancer (OVCA) is the deadliest type of malignant gynecological disease, and previous studies have demonstrated that estrogen receptor β (ERβ) serves important roles in this disease. Aconitine, a toxin produced by the Aconitum plant, displays potent effects against cancers. The aim of the study was to investigate the pharmacological activities and mechanisms of aconitum on OVCA. In the present study, the activity of aconitine in the human OVCA A2780 cell line was investigated. The results ...[more]

PMID: 32705198

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Project description:BackgroundEstrogen receptor β (ERβ) has been reported to play an anti-cancer role in breast cancer, but the regulatory mechanism by which ERβ exerts this effect is not clear. Claudin-6 (CLDN6), a tight junction protein, acts as a tumor suppressor gene in breast cancer. Our previous studies have found that 17β-estradiol (E2) induces CLDN6 expression and inhibits MCF-7 cell migration and invasion, but the underlying molecular mechanisms are still unclear. In this study, we aimed to investigate the role of ERβ in this process and the regulatory mechanisms involved.MethodsPolymerase chain reaction (PCR) and western blot were used to characterize the effect of E2 on the expression of CLDN6 in breast cancer cells. Chromatin immunoprecipitation (ChIP) assays were carried out to confirm the interaction between ERβ and CLDN6. Dual luciferase reporter assays were used to detect the regulatory role of ERβ on the promoter activity of CLDN6. Wound healing and Transwell assays were used to examine the migration and invasion of breast cancer cells. Western blot, immunofluorescence and transmission electron microscopy (TEM) were performed to detect autophagy. Xenograft mouse models were used to explore the regulatory effect of the CLDN6-beclin1 axis on breast cancer metastasis. Immunohistochemistry (IHC) was used to detect ERβ/CLDN6/beclin1 expression in breast cancer patient samples.ResultsHere, E2 upregulated the expression of CLDN6, which was mediated by ERβ. ERβ regulated CLDN6 expression at the transcriptional level. ERβ inhibited the migration and invasion of breast cancer cells through CLDN6. Interestingly, this effect was associated with CLDN6-induced autophagy. CLDN6 positively regulated the expression of beclin1, which is a key regulator of autophagy. Beclin1 knockdown reversed CLDN6-induced autophagy and the inhibitory effect of CLDN6 on breast cancer metastasis. Moreover, ERβ and CLDN6 were positively correlated, and the expression of CLDN6 was positively correlated with beclin1 in breast cancer tissues.ConclusionOverall, this is the first study to demonstrate that the inhibitory effect of ERβ on the migration and invasion of breast cancer cells was mediated by CLDN6, which induced the beclin1-dependent autophagic cascade.

Dataset Information

Antitumor effects of aconitine in A2780 cells via estrogen receptor ??mediated apoptosis, DNA damage and migration.

Publications

Antitumor effects of aconitine in A2780 cells via estrogen receptor β‑mediated apoptosis, DNA damage and migration.

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