Abstract B50: Abrogating cholesterol esterification suppresses pancreatic cancer growth and metastasis mediated by caveolin-1

Abstract

Abstract Pancreatic cancer is one of the most lethal human cancers due to the lack of early diagnosis and its high propensity for metastases. Recent advances in cancer metabolism research have manifested new promises for therapy. However, cholesterol metabolism in pancreatic cancer remains poorly understood. Here, by employing label-free Raman spectromicroscopy, we found an aberrant accumulation of cholesteryl ester (CE) in human pancreatic cancer tissues and cell lines, but not in normal ones. Our biochemical study revealed that accumulation of CE is a consequence of activated PI3K/Akt/mTOR pathway. Pharmaceutical blocking and genetic knockdown of the cholesterol esterification enzyme, acyl-CoA cholesterol acyltransferase-1 (ACAT-1), reduced pancreatic cancer cell proliferation, migration and invasion rate. In an orthotopic mouse model of pancreatic cancer, ACAT-1 inhibition significantly suppressed tumor growth and metastasis. Furthermore, we showed that ACAT-1 inhibition suppressed pancreatic cancer growth and metastasis by induction of intracellular free cholesterol toxicity and down-regulation of Akt and MAPK pathway mediated by caveolin-1. Collectively, our study opens a new opportunity for treating pancreatic cancer by targeting the altered cholesterol metabolism. Citation Format: Junjie Li, Seung-Young Lee, Dongsheng Gu, Bing Song, Shaoxiong Chen, Stephen Konieczny, Timothy Ratliff, Xiaoqi Liu, Jingwu Xie, Ji-Xin Cheng. Abrogating cholesterol esterification suppresses pancreatic cancer growth and metastasis mediated by caveolin-1. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B50.