title: Quantitative proteomic analysis of the inhibitory effects of CIL-102 on viability and invasiveness in human glioma cells.
abstract: CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino)phenyl]ethanone), the major active agent of the alkaloid derivative, has been demonstrated to exert anticancer effects. Herein, we present an investigation focused on the identification of the target(s) of CIL-102's action and the mechanism of its action in apoptotic and anti-invasive pathways. Proteomic approaches were used to purify and identify the protein substrates using 2D difference gel electrophoresis (2D SDS-PAGE) to assess changes in the expression of relevant protein treatment with CIL-102 that resulted in the inhibition of viability and invasion. Our results demonstrate that CIL-102 treatment of U87 cells decreased cell proliferation and invasiveness. CIL-102 dose-dependent induction of apoptosis and inhibitory invasiveness were accompanied by sustained phosphorylation of JNK1/2 and p70S6K as well as generation of the reactive oxygen species. In addition, differential proteins displayed between CIL-102-treated and untreated U87 were determined and validated. There were 11 differentially expressed proteins between the CIL-102-treated and untreated groups. Furthermore, we demonstrated that CIL-102 inhibited cancer cell proliferation and reduced anti-invasion properties by up-regulating the levels of FUMH (Fumarate hydratase). The investigation demonstrated that there was an increase in the cellular levels of FUMH in the CIL-102 reduction in viability and invasion via the activation of JNK1/2 and mTOR signaling modules. NAC administration and shRNA FUMH conferred resistance to CIL-102-inhibited HIF1α and MMP-2 levels via inhibition of JNK1/2 and mTOR activation. We concluded that CIL-102-induced an apoptosis cascade and decreased aggressiveness in astrocytoma cells by modulation of mitochondria function, providing a new mechanism for CIL-102 treatment.
authors.affiliation: Institute of Nursing and Department of Nursing, Chang Gung University of Science and Technology, Taiwan; Chronic Diseases and Health Promotion Research Center, CGUST, Taiwan; Institute of Basic Medicine Science, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chih-Chuan
authors.initials: CC
authors.lastname: Teng
authors.forename: Hsing-Chun
authors.initials: HC
authors.lastname: Kuo
authors.forename: Chun-I
authors.initials: CI
authors.lastname: Sze
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009361:Neoplasm Invasiveness / Q000473:pathology* / Q000517:prevention & control; D040901:Proteomics / Q000379:methods*; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: C510259:1-(4-(furo(2,3-b)quinolin-4-ylamino)phenyl)ethanone; D000970:Antineoplastic Agents; D011804:Quinolines
keywords: CIL-102; Fumarate hydratase; JNK1/2; ROS; p70S6K