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

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57 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 languageEnglish (US)
Pages (from-to)6378-6388
Number of pages11
JournalOncogene
Volume35
Issue number50
DOIs
StatePublished - Dec 15 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    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. (2016). Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene, 35(50), 6378-6388. https://doi.org/10.1038/onc.2016.168