Abstract
Human intrahepatic cholangiocarcinomas are one of the most difficult cancers to treat. In our study, Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme-CoA (HMG-CoA) reductase inhibitor, demonstrated anticancer properties by inhibiting cancer cell proliferation, cell migration and cell adhesion. Lovastatin inhibited the expressions of transforming growth factor (TGF)-β1, cyclooxygenase (COX)-2, and intercellular adhesion molecule (ICAM)-1. Furthermore, lovastatin inhibited the expressions of integrin β1 and integrin β3 but not integrin αv or integrin β5. While Lovastatin's inhibitory effects on TGFβ1, COX2, and ICAM-1 expression were independently controlled by the tumor suppressor LKB1, integrin β3 expression was not affected. Lovastatin's inhibitory effect on cell adhesion was associated with the decreased expression of integrin β3 and cell surface heterodimer integrin αvβ3. Quantitative real time PCR, fluorescent microscopy, and cell migration assays all confirmed that Lovastatin inhibits integrin αvβ3 downstream signaling including FAK activation, and β-catenin, vimentin, ZO-1, and β-actin. Overall, Lovastatin reduced tumor cell proliferation and migration by modifying the expression of genes involved in cell adhesion and other critical cellular processes. Our study highlights novel anti-cancer properties of Lovastatin and supports further exploration of statins in the context of cholangiocarcinoma therapy.
Highlights
Cholangiocarcinomas are malignant tumors of the biliary tract and are the second most common type of primary liver cancer
In order to investigate the anti-proliferation mechanisms associated with lovastatin, several diagnostic markers of cholangiocarcinomas were studied in cells treated with lovastatin (Figure 1A)
These results indicate that lovastatin changes the expression of several genes in cholangiocarcinomas through multiple pathways
Summary
Cholangiocarcinomas are malignant tumors of the biliary tract and are the second most common type of primary liver cancer. Several integrins expressed in cholangiocarcinomas [1,2,3] have been reported in studies related to cancer pathogenesis Those cell surface integrins are known to regulate cell proliferation [4], migration [5], invasion [1, 5], angiogenesis [6], and adhesion [7]. Statins inhibit the production of isoprenoids and block the cholesterol biosynthetic pathway [9] They are www.impactjournals.com/oncotarget used therapeutically to upregulate low-density lipoprotein (LDL) receptor-mediated removal of plasma cholesterol in the liver. In addition to their lipid-lowering properties, statins have been linked to a variety of physiological processes. Studies on lovastatin suggest that it can induce cytoskeletal alterations and modulate adhesion, motility, and proteolysis [15]
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