Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation.

Junjie Li,Jie Tian,Jian-Ting Zhang,Ji-Xin Cheng,Xiaochao Qu,Aamir Ahmad

doi:10.1371/journal.pone.0193318

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.

Highlights

Drug resistance is one of the most challenging problems that hamper the success of complete cancer treatment [1,2]
To further analyze the composition of the lipids inside lipid droplets (LDs), we acquired Raman spectra from LDs in Mia PaCa-2 and G3K cells (Fig 1C), which confirm the presence of cholesteryl ester (CE) in LDs of both cell lines, as evidenced by the peak at ~700 cm-1
Through a quantitative analysis following the protocol established in our previous study [17], we found that LDs in both cell lines contain relatively high level of CE (Fig 1D)

Summary

Introduction

Drug resistance is one of the most challenging problems that hamper the success of complete cancer treatment [1,2]. Compared to the primary resistance, which exists prior to any treatment, acquired resistance represents more challenges for cancer therapy [1]. Extensive studies have deciphered some key mechanisms underlying acquired drug resistance, such as drug inactivation, target alteration, induction of alternative pro-survival pathways, and existence of cancer stem cells [3,4]. Recent evidences further link metabolic alterations to drug resistance in cancer cells. Targeting the reprogrammed metabolism is emerging as a novel strategy to beat the cancer drug resistance [5,6]. Studies have found that targeting glycolytic pathway overcomes resistance to chemotherapies, such as trastuzumab and taxol, in breast cancer [7,8]. Overexpression of pyruvate dehydrogenase kinase 3 (PDK3) promotes a metabolic

Methods

Results

Conclusion