Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation

PLoS One. 2018 Feb 28;13(2):e0193318. doi: 10.1371/journal.pone.0193318. eCollection 2018.

Abstract

Recent advances have recognized metabolic reprogramming as an underlying mechanism for cancer drug resistance. However, the role of cholesterol metabolism in drug resistance remain elusive. Herein, we report an increased accumulation of cholesteryl ester in gemcitabine-resistant pancreatic ductal adenocarcinoma (PDAC) cells. A potent inhibitor of acyl-CoA cholesterol acyltransferase-1 (ACAT-1), avasimibe, effectively suppressed proliferation of gemcitabine-resistant PDAC cells. Combination of avasimibe and gemcitabine showed strong synergistic effect in suppressing PDAC cell viability in vitro and tumor growth in vivo. Immunoblotting analysis suggests downregulation of Akt by avasimibe is likely to contribute to the synergism. Collectively, our study demonstrates a new combinational therapeutic strategy to overcome gemcitabine resistance for PDAC treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cell Survival / drug effects
  • Cholesterol / metabolism*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Esterification / drug effects
  • Female
  • Gemcitabine
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Sterol O-Acyltransferase / antagonists & inhibitors
  • Sterol O-Acyltransferase / metabolism

Substances

  • Enzyme Inhibitors
  • Neoplasm Proteins
  • Deoxycytidine
  • Cholesterol
  • Sterol O-Acyltransferase
  • sterol O-acyltransferase 1
  • Gemcitabine

Grants and funding

This work was supported by DoD Award W81XWH-14-1-0557 to J-XC and the National Natural Science Foundation of China (grant numbers 81227901 and 81530058) to XQ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.