Anlotinib induces apoptosis and second growth/mitosis phase block in cisplatin-resistant ovarian cancer cells via the aurora kinase A/p53 pathway

Author:

Wang Hongli1ORCID,Wang Yu1ORCID

Affiliation:

1. Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China

Abstract

Background Cisplatin (DDP) resistance in ovarian cancer (OC) patients usually leads to treatment failure and increased mortality. Anlotinib has been shown to improve progression-free survival and overall survival in patients with platinum-resistant ovarian cancer, but the mechanism is unclear. This study aims to explore the mechanism by which anlotinib ameliorates platinum resistance in OC cells. Methods Cell viability was detected by the 3-4,5-dimethylthiazol-2,5-diphenyltetrazolium bromide (MTT) method, and the apoptosis rate and changes in the cell cycle distribution were evaluated by flow cytometry. Bioinformatics analysis was used to predict the potential gene target of anlotinib in DDP-resistance SKOV3 cells, and its expression was verifies it by RT-qPCR, western blotting and immunofluorescence staining. Finally, ovarian cancer cells overexpressing AURKA were constructed, and the predicted results were verified by animal experiments. Results Anlotinib effectively induced apoptosis and G2/M arrest in OC cells and decreased the proportion of EdU-positive cells. AURKA was identified as a possible key target of anlotinib for inhibiting tumorigenic behaviors in SKOV3/DDP cells. Through combined immunofluorescence and western blot analyses, it was demonstrated that anlotinib could effectively inhibit the protein expression of AURKA and upregulate the expression of p53/p21, CDK1, and Bax protein. After overexpression of AURKA in OC cells, the induction of apoptosis and G2/M arrest by anlotinib were significantly inhibited. Anlotinib also effectively inhibited the growth of tumors in nude mice injected with OC cells. Conclusions This study demonstrated that anlotinib can induce apoptosis and G2/M arrest in cisplatin-resistant ovarian cancer cells through the AURKA/p53 pathway.

Publisher

SAGE Publications

Subject

Health, Toxicology and Mutagenesis,Toxicology,General Medicine

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