Phosphorylation of Cofilin-1 Enhances Paclitaxel Resistance of Epithelial Ovarian Cancer Cells by Inhibiting Apoptosis.
- Author:
Min LI
1
;
Xu Dong DONG
2
;
Qiu Bo LYU
1
;
Wei ZHANG
3
;
Shuai HUANG
1
;
Chun Xue YANG
4
;
Di CUI
2
;
Hui Ying LAI
5
Author Information
- Publication Type:Journal Article
- Keywords: Apoptosis; Chemo-resistance; Cofilin-1; Epithelial ovarian cancer; Slingshot-1
- MeSH: Antineoplastic Agents, Phytogenic/therapeutic use*; Apoptosis; Carcinoma, Ovarian Epithelial/metabolism*; Cell Line, Tumor; Cofilin 1/metabolism*; Drug Resistance, Neoplasm; Female; Humans; Ovarian Neoplasms/metabolism*; Paclitaxel/therapeutic use*; Phosphoprotein Phosphatases/metabolism*; Phosphorylation
- From: Biomedical and Environmental Sciences 2021;34(6):465-477
- CountryChina
- Language:English
-
Abstract:
Objective:To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells.
Methods:Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1).
Results:High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients.
Conclusion:The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor.