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

Siyuan Jiang,Zhiyuan Xu,Xiaodong Wang,Qinong Ye,Jie Yu,Bingxue Yan,Xuetong Wang,Minxuan Sun,Shan Gao,Zhou Tong,Yunzhao Chen,Dalong Song,Yinmin Gu,Xiaojun Liu,Xiaolu Zhang,Yang Wang

doi:10.1158/0008-5472.can-18-3295

Abstract

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.

Highlights

Several treatments may benefit patients with localized prostate cancer, metastatic prostate cancer remains lethal, and patients with metastatic prostate cancer receive limited benefits from these treatments [1]
We demonstrate that adipocyte plasma membrane-associated protein (APMAP) participates in the cholesterol-induced epithelialto-mesenchymal transition (EMT) of prostate cancer cells by reducing EGFR endocytosis
Antibodies Antibodies against N-cadherin, EPS15R, caveolin-1, flotillin-1, ATP1A1, GAPDH, and vimentin were purchased from Abcam; rabbit anti-APMAP was purchased from Proteintech Group; mouse monoclonal anti-APMAP was purchased from OriGene; anti-mouse secondary antibody (HRP) for the Western blotting detection immunoprecipitation proteins was purchased from Abcam; preabsorbed Alexa Fluor 488- and 555-conjugated secondary antibodies were purchased from Abbkine; preabsorbed Alexa Fluor 647-conjugated secondary antibodies were purchased from Jackson; and the other 10 antibodies were purchased from Cell Signaling Technology

Summary

Introduction

Several treatments may benefit patients with localized prostate cancer, metastatic prostate cancer remains lethal, and patients with metastatic prostate cancer receive limited benefits from these treatments [1]. Cancer cell metastasis requires a process known as the epithelialto-mesenchymal transition (EMT), in which epithelial cells lose cell–cell adhesion properties and cell polarity and undergo reorganization of their cytoskeleton, dramatic changes in morphology, and reprogramming of gene expression [3]. This process is driven by activation of and/or cross-talk between several signaling pathways [4,5,6], including the TGFb, EGF/EGFR and androgen receptor (AR) signaling pathways [7, 8]. The underlying molecular mechanisms of EMT in prostate cancer remain poorly understood. The effect of cholesterol on EMT and the underlying mechanism are unclear in prostate cancer

Methods

Results

Conclusion