Research Article: Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation

Date Published: February 28, 2018

Publisher: Public Library of Science

Author(s): Junjie Li, Xiaochao Qu, Jie Tian, Jian-Ting Zhang, Ji-Xin Cheng, Aamir Ahmad.

http://doi.org/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.

Partial Text

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]. Similarly, overexpression of pyruvate dehydrogenase kinase 3 (PDK3) promotes a metabolic switch from mitochondrial respiration to glycolysis under hypoxia condition and increases drug resistance in cervical and colon cancer [9,10]. Besides, fatty acid synthase (FASN), a key enzyme in the fatty acid synthesis pathway, was reported to be involved in multiple drug resistance, such as docetaxel/trastuzumab resistance in breast cancer and gemcitabine or radiation resistance in pancreatic cancer [11–15]. Despite these advances, cholesterol metabolism remains an underexplored area in terms of drug resistance in cancers.

Pancreatic cancer (mostly PDAC) remains the fourth leading cause of cancer death in 2018, with 55,440estimated new cases and 44,330estimated new deaths [25]. Since 1996, gemcitabine has been used as the cornerstone for treating this deadly disease, despite its modest overall effects to the patients. Development of resistance to gemcitabine in almost 100% of the patients further hampers its clinical benefits. To develop an effective therapeutic strategy to target gemcitabine resistance represents an unmet need in PDAC treatment. In this study, for the first time we showed that cholesterol metabolism is related to gemcitabine resistance in PDAC. Inhibitor of cholesterol esterification, avasimibe, synergistically suppresses PDAC cell proliferation with gemcitabine, suggesting it as a potential anti-cancer agent for aggressive PDAC treatment.

 

Source:

http://doi.org/10.1371/journal.pone.0193318

 

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