LDLR promotes autophagy‐mediated cisplatin resistance in ovarian cancer associated with the PI3K/AKT/mTOR signaling pathway

PI3K/AKT/mTOR通路 自噬 蛋白激酶B 癌症研究 细胞凋亡 细胞生长 活力测定 低密度脂蛋白受体 信号转导 医学 细胞生物学 化学 生物 内科学 生物化学 脂蛋白 胆固醇
作者
Lei Liu,Yuhui Sun,Ran An,Rongjie Cheng,Nan Li,Jianhua Zheng
出处
期刊:Kaohsiung Journal of Medical Sciences [Wiley]
卷期号:39 (8): 779-788 被引量:10
标识
DOI:10.1002/kjm2.12696
摘要

Autophagy is one of the underlying causes of resistance to many antitumor drugs, including cisplatin (DDP). The low-density lipoprotein receptor (LDLR) is a regulator of ovarian cancer (OC) progression. However, whether LDLR regulates DDP resistance in OC via autophagy-related pathways remains unclear. LDLR expression was measured by quantitative real-time PCR, western blot (WB) and IHC staining. A Cell Counting Kit 8 assay was employed to evaluate DDP resistance and cell viability, and flow cytometry was used to assess apoptosis. WB analysis was employed to evaluate the expression of autophagy-related proteins and PI3K/AKT/mTOR signaling pathway proteins. The autophagolysosomes and the fluorescence intensity of LC3 were observed by transmission electron microscopy and immunofluorescence staining, respectively. A xenograft tumor model was established to explore the role of LDLR in vivo. LDLR was highly expressed in OC cells, which was correlated with disease progression. In DDP-resistant OC cells, high LDLR expression was related to DDP resistance and autophagy. Downregulation of LDLR repressed autophagy and growth in DDP-resistant OC cell lines by activating the PI3K/AKT/mTOR pathway, and these effects were eliminated by an mTOR inhibitor. In addition, LDLR knockdown also reduced OC tumor growth by suppressing autophagy associated with the PI3K/AKT/mTOR pathway. LDLR promoted autophagy-mediated DDP resistance in OC associated with the PI3K/AKT/mTOR pathway, indicating that LDLR might be a new target to prevent DDP resistance in OC patients.
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