title: Smh-3 induces G(2)/M arrest and apoptosis through calcium‑mediated endoplasmic reticulum stress and mitochondrial signaling in human hepatocellular carcinoma Hep3B cells.
abstract: In the present study, we investigated the antitumor effects of Smh-3 on the viability, cell cycle and apoptotic cell death in human hepatocellular carcinoma Hep3B cells in vitro. We also investigated the molecular mechanisms involved in the effects of Smh-3 on human hepatoma Hep3B cells, including the effects on protein and mRNA levels which were determined by western blotting and DNA microarray methods, respectively. The results demonstrated that Smh-3 induced growth inhibition, cell morphological changes and induction of G(2)/M arrest and apoptosis in Hep3B cells. DNA microarray assay identified numerous differentially expressed genes related to angiogenesis, autophagy, calcium-mediated ER stress signaling, cell adhesion, cell cycle and mitosis, cell migration, cytoskeleton organization, DNA damage and repair, mitochondrial-mediated apoptosis and cell signaling pathways. Furthermore, Smh-3 inhibited CDK1 activity, mitochondrial membrane potential (ΔΨm) and increased the cytosolic Ca(2+) release and caspase-4, caspase-9 and caspase-3 activities in Hep3B cells. Western blot analysis demonstrated that Smh-3 increased the protein levels of caspase-4 and GADD153 that may lead to ER stress and consequently apoptosis in Hep3B cells. Taken together, Smh-3 acts against human hepatocellular carcinoma Hep3B cells in vitro through G(2)/M phase arrest and induction of calcium-mediated ER stress and mitochondrial-dependent apoptotic signaling pathways.
authors.affiliation: Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung 404, Taiwan, ROC.
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Jo-Hua
authors.initials: JH
authors.lastname: Chiang
authors.forename: Ming-Hua
authors.initials: MH
authors.lastname: Chen
authors.forename: Li-Jiau
authors.initials: LJ
authors.lastname: Huang
authors.forename: Ho-Yu
authors.initials: HY
authors.lastname: Ha
authors.forename: Shinji
authors.initials: S
authors.lastname: Fushiya
authors.forename: Sheng-Chu
authors.initials: SC
authors.lastname: Kuo
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011759:Pyrrolidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C559958:2-(3-(methylamino)phenyl)-6-(pyrrolidin-1-yl)quinolin-4-one; D000970:Antineoplastic Agents; D011759:Pyrrolidines; D015363:Quinolones; D016203:CDC2 Protein Kinase; C093516:CASP4 protein, human; D053148:Caspase 3; D053453:Caspase 9; D053471:Caspases, Initiator; D002118:Calcium