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Cholesterol esterification inhibition suppresses prostate cancer metastasis by impairing the Wnt/β-catenin pathway (Conference Presentation)
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Paper Abstract

Experimental design: We used Raman spectroscopic analysis of human prostate cancer patient tissues to characterize composition of lipid droplets in the metastatic lesions. The therapeutic efficacy was tested in prostate cancer orthotopic and intra-cardiac injection mouse models. Gene expression profiling was used to identify genes that are affected by cholesteryl ester depletion. Additionally, immunoblotting, immunofluorescent staining and transwell assay were used to further verify inactivation of Wnt/β-catenin pathway by cholesteryl ester depletion. Stimulated Raman scattering microscopy and mass spectrometry were used to assess lipogenic potential of cholesteryl ester-depleted prostate cancer cells. Results: We observed accumulation of cholesteryl ester in metastatic lesions of human prostate cancer patient tissues. Inhibiting cholesterol esterification significantly reduced the number of metastatic clusters by 50% in the prostate cancer orthotopic mouse model. We showed suppression of metastatic tumor growth in the intra-cardiac injection model without observable toxicity to the mice. The mechanism study further supports that cholesteryl ester depletion suppresses metastasis by upregulation of regulators that negatively impact prostate cancer metastasis. Notably, Wnt/β-catenin is downregulated upon cholesteryl ester depletion, and we found evidence suggesting that cholesteryl ester depletion significantly blocks secretion of Wnt3a through reduction of monounsaturated fatty acid levels, which limits Wnt3a acylation. In conclusion, we demonstrate that targeting cholesterol esterification can treat metastatic prostate cancer effectively with minimum toxicity.

Paper Details

Date Published: 4 March 2019
Proc. SPIE 10873, Optical Biopsy XVII: Toward Real-Time Spectroscopic Imaging and Diagnosis, 1087307 (4 March 2019); doi: 10.1117/12.2506635
Show Author Affiliations
Hyeon Jeong Lee, Boston Univ. (United States)
Ji-Xin Cheng, Boston Univ. (United States)

Published in SPIE Proceedings Vol. 10873:
Optical Biopsy XVII: Toward Real-Time Spectroscopic Imaging and Diagnosis
Robert R. Alfano; Stavros G. Demos; Angela B. Seddon, Editor(s)

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