TY - JOUR
T1 - Cholesterol esterification inhibition suppresses prostate cancer metastasis by impairing the Wnt/b-catenin pathway
AU - Lee, Hyeon Jeong
AU - Li, Jie
AU - Vickman, Renee E.
AU - Li, Junjie
AU - Liu, Rui
AU - Durkes, Abigail C.
AU - Elzey, Bennett D.
AU - Yue, Shuhua
AU - Liu, Xiaoqi
AU - Ratliff, Timothy L.
AU - Cheng, Ji Xin
N1 - Publisher Copyright:
© 2018 AACR.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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/b-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.
AB - 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/b-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.
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U2 - 10.1158/1541-7786.MCR-17-0665
DO - 10.1158/1541-7786.MCR-17-0665
M3 - Article
C2 - 29545473
AN - SCOPUS:85048246108
SN - 1541-7786
VL - 16
SP - 974
EP - 985
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 6
ER -
