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

Shuhua Yue; Junjie Li; Seung Young Lee; Hyeon Jeong Lee; Tian Shao; Bing Song; Liang Cheng; Timothy A. Masterson; Xiaoqi Liu; Timothy L. Ratliff; Ji Xin Cheng

doi:10.1016/j.cmet.2014.01.019

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

Shuhua Yue, Junjie Li, Seung Young Lee, Hyeon Jeong Lee, Tian Shao, Bing Song, Liang Cheng, Timothy A. Masterson, Xiaoqi Liu, Timothy L. Ratliff, Ji Xin Cheng

Research output: Contribution to journal › Article › peer-review

655 Scopus citations

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.

Original language	English
Pages (from-to)	393-406
Number of pages	14
Journal	Cell Metabolism
Volume	19
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2014.01.019
State	Published - Mar 4 2014

Bibliographical note

Funding Information:
This work was supported by the Walther Cancer Foundation (T.L.R. and J.-X.C.), NIH R21 CA182608 (J.-X.C.), NIH R01 CA157429 and NSF 1049693 (X.L.), and Department of Defense Predoctoral Traineeship Award BC100572 (S.Y.). We greatly appreciate the help from Michael O. Koch, Kimberly K. Buhman, Chang-Deng Hu, Scott A. Crist, James C. Fleet, and Beth R. Pflug for their insightful comments; R. Graham Cooks for sharing the tissue specimens; Zhiguo Li for his expert help in the western blot experiment; and Sandra Torregrosa-Allen and Leelyn Chong for their expert help in the animal experiments.

Funding

This work was supported by the Walther Cancer Foundation (T.L.R. and J.-X.C.), NIH R21 CA182608 (J.-X.C.), NIH R01 CA157429 and NSF 1049693 (X.L.), and Department of Defense Predoctoral Traineeship Award BC100572 (S.Y.). We greatly appreciate the help from Michael O. Koch, Kimberly K. Buhman, Chang-Deng Hu, Scott A. Crist, James C. Fleet, and Beth R. Pflug for their insightful comments; R. Graham Cooks for sharing the tissue specimens; Zhiguo Li for his expert help in the western blot experiment; and Sandra Torregrosa-Allen and Leelyn Chong for their expert help in the animal experiments.

Funders	Funder number
National Science Foundation Arctic Social Science Program	1049693
National Science Foundation Arctic Social Science Program
National Institutes of Health (NIH)	R21 CA182608
National Institutes of Health (NIH)
U.S. Department of Defense	BC100572
U.S. Department of Defense
National Childhood Cancer Registry – National Cancer Institute	R01CA157429
National Childhood Cancer Registry – National Cancer Institute
Walther Cancer Foundation

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2014.01.019

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title = "Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness",

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.",

author = "Shuhua Yue and Junjie Li and Lee, {Seung Young} and Lee, {Hyeon Jeong} and Tian Shao and Bing Song and Liang Cheng and Masterson, {Timothy A.} and Xiaoqi Liu and Ratliff, {Timothy L.} and Cheng, {Ji Xin}",

note = "Funding Information: This work was supported by the Walther Cancer Foundation (T.L.R. and J.-X.C.), NIH R21 CA182608 (J.-X.C.), NIH R01 CA157429 and NSF 1049693 (X.L.), and Department of Defense Predoctoral Traineeship Award BC100572 (S.Y.). We greatly appreciate the help from Michael O. Koch, Kimberly K. Buhman, Chang-Deng Hu, Scott A. Crist, James C. Fleet, and Beth R. Pflug for their insightful comments; R. Graham Cooks for sharing the tissue specimens; Zhiguo Li for his expert help in the western blot experiment; and Sandra Torregrosa-Allen and Leelyn Chong for their expert help in the animal experiments. ",

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AU - Song, Bing

AU - Cheng, Liang

AU - Masterson, Timothy A.

AU - Liu, Xiaoqi

AU - Ratliff, Timothy L.

AU - Cheng, Ji Xin

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N2 - 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.

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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