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Inhibition of VEGFA Increases the Sensitivity of Ovarian Cancer Cells to Chemotherapy by Suppressing VEGFA-Mediated Autophagy.

ABSTRACT: Background:Ovarian cancer (OvCa) is the leading cause of death of gynecological malignancies worldwide. Vascular endothelial growth factor A (VEGFA), the most potent angiogenic factor, is responsible for tumor growth and angiogenesis, but its role in OvCa chemotherapy resistance remains unclear. Methods:RT-PCR and Western blot were used to detect VEGFA expression in tumor cells and normal ovarian surface epithelial cells. Gene Ontology (GO) enrichment analysis was used to analyze GO terms correlated with VEGFA. In in vitro experiments, we knockdown VEGFA in tumor cells and detected the tumor cell viability and apoptosis after chemotherapy drug treatment by MTT assay and flow cytometry. Western blot was used to detect autophagy and apoptosis related proteins. Results:We proved that VEGFA was highly expressed in tumor cells comparted with normal ovarian surface epithelial cells, and enriched GO analysis of VEGFA showed that VEGFA was involved in anti-apoptotic process. Further in vitro experiments confirmed that expression of VEGFA was correlated with chemotherapy resistance and this effect was mediated by autophagy. Meanwhile tumor cells treated with chemotherapy drugs also promoted the expression of VEGFA. Knockdown VEGFA inhibited autophagy of tumor cells and thus potents the killing efficiency in DDP resistant tumor cells and this effect could be reversed by the addition of recombinant VEGFA. Conclusion:Taken together, our study demonstrates that VEGFA is involved in anti-apoptosis of tumor cells to chemotherapy, killing partly through autophagy, indicating that VEGFA may serve as a potential target to improve chemotherapy treatment.

SUBMITTER: Li X

PROVIDER: S-EPMC7443464 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Inhibition of VEGFA Increases the Sensitivity of Ovarian Cancer Cells to Chemotherapy by Suppressing VEGFA-Mediated Autophagy.

Li Xia X Hu Zhenhua Z Shi Huirong H Wang Cong C Lei Jia J Cheng Yan Y

OncoTargets and therapy 20200818

<h4>Background</h4>Ovarian cancer (OvCa) is the leading cause of death of gynecological malignancies worldwide. Vascular endothelial growth factor A (VEGFA), the most potent angiogenic factor, is responsible for tumor growth and angiogenesis, but its role in OvCa chemotherapy resistance remains unclear.<h4>Methods</h4>RT-PCR and Western blot were used to detect VEGFA expression in tumor cells and normal ovarian surface epithelial cells. Gene Ontology (GO) enrichment analysis was used to analyze ...[more]

PMID: 32884298

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Project description:High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy. However, the molecular mechanisms underlying HGSOC development, progression, chemotherapy insensitivity and resistance remain unclear. Two independent GEO datasets, including the gene expression profile of primary ovarian carcinoma and normal controls, were analyzed to identify genes related to HGSOC development and progression. A KEGG pathway analysis of the differentially expressed genes (DEGs) revealed that the cell cycle pathway was the most enriched pathway, among which TTK protein kinase (TTK) was the only gene with a clinical-grade inhibitor that has been investigated in a clinical trial but had not been studied in HGSOC. TTK was also upregulated in cisplatin-resistant ovarian cancer cells from two other datasets. TTK is a regulator of spindle assembly checkpoint signaling, playing an important role in cell cycle control and tumorigenesis in various cancers. However, the function and regulatory mechanism of TTK in HGSOC remain to be determined. In this study, we observed TTK upregulation in patients with HGSOC. High TTK expression was related to a poor prognosis. Genetic and pharmacological inhibition of TTK impeded the proliferation of ovarian cancer cells by disturbing cell cycle progression and increasing apoptosis. TTK silencing increased cisplatin sensitivity by activating the mammalian target of rapamycin (mTOR) complex to further suppress cisplatin-induced autophagy in vitro. In addition, the enhanced sensitivity was partially diminished by rapamycin-mediated inhibition of mTOR in TTK knockdown cells. Furthermore, TTK knockdown increased the toxicity of cisplatin in vivo by decreasing autophagy. These findings suggest that the administration of TTK inhibitors in combination with cisplatin may lead to improved response rates to cisplatin in patients with HGSOC presenting high TTK expression. In summary, our study may provide a theoretical foundation for using the combination therapy of cisplatin and TTK inhibitors as a treatment for HGSOC in the future.

Dataset Information

Inhibition of VEGFA Increases the Sensitivity of Ovarian Cancer Cells to Chemotherapy by Suppressing VEGFA-Mediated Autophagy.

Publications

Inhibition of VEGFA Increases the Sensitivity of Ovarian Cancer Cells to Chemotherapy by Suppressing VEGFA-Mediated Autophagy.

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