Cholesterol Induces Epithelial-to-Mesenchymal Transition of Prostate Cancer Cells by Suppressing Degradation of EGFR through APMAP

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 12; pp. 3063 - 3075
• Main Authors: Jiang, Siyuan, Wang, Xuetong, Song, Dalong, Liu, XiaoJun, Gu, Yinmin, Xu, Zhiyuan, Wang, Xiaodong, Zhang, Xiaolu, Ye, Qinong, Tong, Zhou, Yan, BingXue, Yu, Jie, Chen, Yunzhao, Sun, Minxuan, Wang, Yang, Gao, Shan
• Format: Journal Article
• Language: English
• Published: United States 15.06.2019
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Case-Control Studies; Cell Proliferation; Cholesterol - pharmacology; Epithelial-Mesenchymal Transition - drug effects; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; Male; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred NOD; Mice, SCID; Prognosis; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Proteolysis - drug effects; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• DOI: 10.1158/0008-5472.CAN-18-3295
• ISSN: 0008-5472; 1538-7445

Cholesterol increases the risk of aggressive prostate cancer and has emerged as a potential therapeutic target for prostate cancer. The functional roles of cholesterol in prostate cancer metastasis are not fully understood. Here, we found that cholesterol induces the epithelial-to-mesenchymal transition (EMT) through extracellular-regulated protein kinases 1/2 pathway activation, which is mediated by EGFR and adipocyte plasma membrane-associated protein (APMAP) accumulation in cholesterol-induced lipid rafts. Mechanistically, APMAP increases the interaction with EGFR substrate 15-related protein (EPS15R) to inhibit the endocytosis of EGFR by cholesterol, thus promoting cholesterol-induced EMT. Both the mRNA and protein levels of APMAP are upregulated in clinical prostate cancer samples. Together, these findings shed light onto an APMAP/EPS15R/EGFR axis that mediates cholesterol-induced EMT of prostate cancer cells. SIGNIFICANCE: This study delineates the molecular mechanisms by which cholesterol increases prostate cancer progression and demonstrates that the binding of cholesterol-induced APMAP with EPS15R inhibits EGFR internalization and activates ERK1/2 to promote EMT. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/12/3063/F1.large.jpg.