Phosphorylation of Cofilin-1 Enhances Paclitaxel Resistance of Epithelial Ovarian Cancer Cells by Inhibiting Apoptosis.

Min LI; Xu Dong DONG; Qiu Bo LYU; Wei ZHANG; Shuai HUANG; Chun Xue YANG; Di CUI; Hui Ying LAI

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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
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1. Department of Obstetrics and Gynecology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
2. Department of Obstetrics, the First People's Hospital of Yunnan Province, Kunming 650032, Yunnan, China.
3. Department of Pathology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
4. Peking University Health Science Center, Beijing 100069, China.
5. Clinical Laboratory, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
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.