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Cell Metab. 2014 Mar 4;19(3):393-406. doi: 10.1016/j.cmet.2014.01.019.

Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness.

Author information

1
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
2
Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA.
3
Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA.
4
Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
5
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
6
Department of Urology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
7
Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
8
Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
9
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA. Electronic address: jcheng@purdue.edu.

Abstract

Altered lipid metabolism is increasingly recognized as a signature of cancer cells. Enabled by label-free Raman spectromicroscopy, we performed quantitative analysis of lipogenesis at single-cell level in human patient cancerous tissues. Our imaging data revealed an unexpected, aberrant accumulation of esterified cholesterol in lipid droplets of high-grade prostate cancer and metastases. Biochemical study showed that such cholesteryl ester accumulation was a consequence of loss of tumor suppressor PTEN and subsequent activation of PI3K/AKT pathway in prostate cancer cells. Furthermore, we found that such accumulation arose from significantly enhanced uptake of exogenous lipoproteins and required cholesterol esterification. Depletion of cholesteryl ester storage significantly reduced cancer proliferation, impaired cancer invasion capability, and suppressed tumor growth in mouse xenograft models with negligible toxicity. These findings open opportunities for diagnosing and treating prostate cancer by targeting the altered cholesterol metabolism.

PMID:
24606897
PMCID:
PMC3969850
DOI:
10.1016/j.cmet.2014.01.019
[Indexed for MEDLINE]
Free PMC Article

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