Journal
CANCER RESEARCH
Volume 79, Issue 12, Pages 3063-3075Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-3295
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Funding
- National Key R&D Program of China [2016YFC1302100]
- National Natural Science Foundation of China [81773023, 81472827, 81802526]
- Hundred-Talent Program and Frontier Research Program of Chinese Academy of Sciences [QYZDB-SSW-SMC038]
- Natural Science Foundationof Jiangsu Province [BK20160174]
- Scientific and Technological Innovation Program of Shanxi Transformation and Comprehensive Reform Demonstration Area of antibody screening and development platform [2017KJCX01]
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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.
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