Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

J. Li; D. Gu; S. S.Y. Lee; B. Song; S. Bandyopadhyay; S. Chen; S. F. Konieczny; T. L. Ratliff; X. Liu; J. Xie; J. X. Cheng

doi:10.1038/onc.2016.168

Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

J. Li, D. Gu, S. S.Y. Lee, B. Song, S. Bandyopadhyay, S. Chen, S. F. Konieczny, T. L. Ratliff, X. Liu, J. Xie, J. X. Cheng

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

248 Scopus citations

Abstract

Cancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.

Original language	English
Pages (from-to)	6378-6388
Number of pages	11
Journal	Oncogene
Volume	35
Issue number	50
DOIs	https://doi.org/10.1038/onc.2016.168
State	Published - Dec 15 2016

Bibliographical note

Publisher Copyright:
© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Funding

We greatly appreciate the help from Dr Tian Shao, Dr Zhiguo Li for their technical support. This work was supported by Indiana State CTSI grant 106564 to JX and JXC, NIH CA182608 to JXC, NCI R25CA128770 CPIP fellowship to JL, NIH CA124586 to SFK, and CA155086 to JX, and NIH grant P30CA023168 to Purdue University Center for Cancer Research for publications.

Funders	Funder number
Indiana State CTSI	106564, CA182608
National Institutes of Health (NIH)	CA155086
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	R01CA124586, R25CA128770, P30CA023168
National Childhood Cancer Registry – National Cancer Institute

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

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

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10.1038/onc.2016.168

Cite this

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abstract = "Cancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.",

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AU - Gu, D.

AU - Lee, S. S.Y.

AU - Song, B.

AU - Bandyopadhyay, S.

AU - Chen, S.

AU - Konieczny, S. F.

AU - Ratliff, T. L.

AU - Liu, X.

AU - Xie, J.

AU - Cheng, J. X.

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N2 - Cancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.

AB - Cancer cells are known to execute reprogramed metabolism of glucose, amino acids and lipids. Here, we report a significant role of cholesterol metabolism in cancer metastasis. By using label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester in human pancreatic cancer specimens and cell lines, mediated by acyl-CoA cholesterol acyltransferase-1 (ACAT-1) enzyme. Expression of ACAT-1 showed a correlation with poor patient survival. Abrogation of cholesterol esterification, either by an ACAT-1 inhibitor or by shRNA knockdown, significantly suppressed tumor growth and metastasis in an orthotopic mouse model of pancreatic cancer. Mechanically, ACAT-1 inhibition increased intracellular free cholesterol level, which was associated with elevated endoplasmic reticulum stress and caused apoptosis. Collectively, our results demonstrate a new strategy for treating metastatic pancreatic cancer by inhibiting cholesterol esterification.

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Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

Access to Document

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