title: Anti-cancer effects of naturally occurring compounds through modulation of signal transduction and miRNA expression in human colon cancer cells.
abstract: Much evidence indicates that various naturally occurring compounds have an anti-cancer effect, but the detailed mechanisms are not well understood. In this study, we selected anti-cancer phytochemicals such as epigallocatechin-3-gallate (EGCG), resveratrol (RES) and α-mangostin (α-M), all of which are well-characterized chemopreventive agents. We sought to elucidate the mechanism of their anti-cancer effects and the synergistic effects obtained by combined treatment with the anti-cancer drug 5-fluorouracil (5-FU) in three human colon cancer cell lines. The numbers of viable cells were consistently decreased by the treatment with EGCG, RES or α-M at more than 10 μM in all three cell lines tested. All compounds mainly induced apoptosis and suppressed the PI3K/Akt signaling pathway. Additionally, α-M, which had the greatest PI3K/Akt-suppressing activity, also suppressed MAP kinase (MAPK)/Erk1/2 signaling. Importantly, the combination treatment with RES and 5-FU induced a remarkably synergistic enhancement of growth inhibition and apoptosis through the additional suppression of the MAPK/Erk1/2 signaling pathway in colon cancer DLD-1 cells. Interestingly, RES increased the intracellular expression level of miR-34a, which down-regulated the target gene E2F3 and its downstream Sirt1, resulting in growth inhibition. These findings indicate that these compounds functioned as chemosensitizers when combined with anti-cancer drugs through the modulation of apoptotic and growth-related signaling pathways. Also, RES exerted its anti-cancer activity in part through a newly defined mechanism, i.e., the miR-34a/E2F3/Sirt1 cascade.
authors: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Graduate School of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
authors: Minami
authors: M
authors: Kumazaki
authors: Shunsuke
authors: S
authors: Noguchi
authors: Yuki
authors: Y
authors: Yasui
authors: Junya
authors: J
authors: Iwasaki
authors: Haruka
authors: H
authors: Shinohara
authors: Nami
authors: N
authors: Yamada
authors: Yukihiro
authors: Y
authors: Akao
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002392:Catechin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000627:therapeutic use*; D044004:Xanthones / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D013267:Stilbenes; D044004:Xanthones; D002392:Catechin; C045651:epigallocatechin gallate; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000077185:Resveratrol; C021053:mangostin
keywords: Anti-cancer drug; Anti-cancer effect; Apoptosis; Phytochemicals; Resveratrol; miR-34a