Cholesterol Esterification Inhibition Suppresses Prostate Cancer Metastasis by Impairing the Wnt/β-catenin Pathway
Abstract
Dysregulation of cholesterol is a common characteristic of human cancers including prostate cancer. This study observed an aberrant accumulation of cholesteryl ester in metastatic lesions using Raman spectroscopic analysis of lipid droplets in human prostate cancer patient tissues. Inhibition of cholesterol esterification in prostate cancer cells significantly suppresses the development and growth of metastatic cancer lesions in both orthotopic and intracardiac injection mouse models. Gene expression profiling reveals that cholesteryl ester depletion suppresses the metastatic potential through upregulation of multiple regulators that negatively impact metastasis. In addition, Wnt/β-catenin, a vital pathway for metastasis, is downregulated upon cholesteryl ester depletion. Mechanistically, inhibition of cholesterol esterification significantly blocks secretion of Wnt3a through reduction of monounsaturated fatty acid levels, which limits Wnt3a acylation. These results collectively validate cholesterol esterification as a novel metabolic target for treating metastatic prostate cancer. Mol Cancer Res; 16(6); 974–85. ©2018 AACR.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 31, 2018
- Source ID
- 10.1158/1541-7786.mcr-17-0665
Entities
People
- Abigail C. Durkes
- Bennett D. Elzey
- Hyeon Jeong Lee
- Ji-Xin Cheng
- Jie Li
- Junjie Li
- Renee E Vickman
- Rui Liu
- Shuhua Yue
- Timothy L Ratliff
- Xiaoqi Liu
Organizations
- Beihang University
- Boston University
- National Institutes of Health
- Purdue University
- United States Department of Defense