Abstract LB-C03: Lovastatin induced anti-proliferation through multi-pathways in human intrahepatic cholangiocarcinoma

Abstract

Abstract Lovastatin induced anti-proliferation through multi-pathways in human intrahepatic cholangiocarcinoma. Yu-Chen Yang1, Hung-Yun Lin1, Chun A Changou1,2,3, Chun-Han Chen1, Yun-Ru Liu4, Jinghan Wang5, Xiaoqing Jiang5, Yun Yen1* 1PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.2Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.3Core Facility, Taipei Medical University, Taipei, Taiwan. 4Office of Human Research, Taipei Medical University, Taipei, Taiwan and 5The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China. Abstract Human intrahepatic cholangiocarcinomas are one of the most difficult cancers to treat. Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme-CoA (HMG-CoA) reductase inhibitor, exhibits anticancer properties. In this study, lovastatin inhibited cell proliferation, cell migration and cell adhesion. Results showed lovastatin inhibited the gene expressions of integrin β1 and integrin β3 but not integrin αv or integrin β5. Furthermore, gene expressions of transforming growth factor (TGF)-β1, cyclooxygenase (COX)-2 and intercellular adhesion molecule (ICAM)-1 were inhibited by lovastatin. Also, the cholesterol-depleting agent, methyl-beta-cyclodextrin (MβCD), reduced the expression of β3 integrin, but not that of the other genes in either cancer cell line. The lovastatin-induced inhibitory effects on expressions of TGFβ1, COX2, and ICAM-1 were positively controlled by the tumor suppressor, LKB1; however, the inhibition of integrin β3 by lovastatin was negatively affected by LKB1. The inhibitory effect of lovastatin on cell adhesion was associated with decreased expression of integrin β3 and the presentation of cell surface heterodimer integrin αvβ3. Furthermore, lovastatin strongly inhibited integrin αvβ3 downstream FAK activation, and the expression of β-catenin, vimentin, ZO-1, and β-actin. Therefore, in addition to the cholesterol-depleting effect, lovastatin modified the expressions of cell adhesion molecules leading to reduced tumor cell proliferation and migration. These advantageous effects of lovastatin may be mediated by blocking integrin β3 signaling suggesting a novel treatment option for cholangiocarcinomas. Keywords: Bile duct cancer, HMG-CoA reductase inhibitor, Integrin, LKB1, TGF-β1 Citation Format: Yu-Chen Yang, Hung-Yun Lin. Lovastatin induced anti-proliferation through multi-pathways in human intrahepatic cholangiocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C03.