Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer

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 canc...

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Autores principales: Li, J, Gu, D, Lee, S S-Y, Song, B, Bandyopadhyay, S, Chen, S, Konieczny, S F, Ratliff, T L, Liu, X, Xie, J, Cheng, J-X
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Original Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093084/
https://www.ncbi.nlm.nih.gov/pubmed/27132508
http://dx.doi.org/10.1038/onc.2016.168
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author Li, J
Gu, D
Lee, S S-Y
Song, B
Bandyopadhyay, S
Chen, S
Konieczny, S F
Ratliff, T L
Liu, X
Xie, J
Cheng, J-X
author_facet Li, J
Gu, D
Lee, S S-Y
Song, B
Bandyopadhyay, S
Chen, S
Konieczny, S F
Ratliff, T L
Liu, X
Xie, J
Cheng, J-X
author_sort Li, J
collection PubMed
description 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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spelling pubmed-50930842016-12-16 Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer Li, J Gu, D Lee, S S-Y Song, B Bandyopadhyay, S Chen, S Konieczny, S F Ratliff, T L Liu, X Xie, J Cheng, J-X Oncogene Original Article 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. Nature Publishing Group 2016-12-15 2016-05-02 /pmc/articles/PMC5093084/ /pubmed/27132508 http://dx.doi.org/10.1038/onc.2016.168 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Li, J
Gu, D
Lee, S S-Y
Song, B
Bandyopadhyay, S
Chen, S
Konieczny, S F
Ratliff, T L
Liu, X
Xie, J
Cheng, J-X
Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer
title Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer
title_full Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer
title_fullStr Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer
title_full_unstemmed Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer
title_short Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer
title_sort abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093084/
https://www.ncbi.nlm.nih.gov/pubmed/27132508
http://dx.doi.org/10.1038/onc.2016.168
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