title: ZM336372, a Raf-1 activator, causes suppression of proliferation in a human hepatocellular carcinoma cell line.
abstract: Hepatocellular carcinoma has been described to exhibit characteristics similar to that of neuroendocrine tumors (NETs). This includes similar anti-neoplastic responses to extracellular signal-regulated kinase (ERK) activation. NET cells and HepG2 cells have both shown growth inhibition with ERK activation. ZM336372, a Raf-1 activating agent, has been shown to cause growth inhibition and suppression of hormone secretion in a neuroendocrine cell line. Here we examine treatment of the HepG2 cell line with ZM336732 to determine if a similar anti-proliferative response will be obtained. HepG2 cells were treated with ZM336372 or solvent (dimethyl sulfoxide). The resulting effect on the proliferation was measured using the 3,4-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Western blot analysis was performed to examine the activation of the Raf-1/mitogen-activated protein kinase kinase/ERK pathway, chromogranin A production, and p21CIP1 level. Growth inhibition was observed with ZM336372 in a dose-dependent fashion. Minimal baseline phosphorylation of ERK 1/2 was observed; however, activation was observed after treatment with ZM336372. Chromogranin A secretion was suppressed due to treatment with ZM336372. A dose-dependent up-regulation of p21CIP1 was observed in response to ZM336372 treatment. ZM336372 causes growth inhibition, suppression of hormone secretion, and up-regulation of cell cycle inhibitors in a human hepatocellular carcinoma cell line, similar to that previously seen in NETs.
authors.affiliation: Department of Medicine, University of Wisconsin, K4/528, Madison, WI 53792, USA.
authors.forename: Dustin
authors.initials: D
authors.lastname: Deming
authors.forename: Peter
authors.initials: P
authors.lastname: Geiger
authors.forename: Herbert
authors.initials: H
authors.lastname: Chen
authors.forename: Abram
authors.initials: A
authors.lastname: Vaccaro
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Kunnimalaiyaan
authors.forename: Kyle
authors.initials: K
authors.lastname: Holen
mesh_terms: D001549:Benzamides / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D053379:Chromogranin A / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D015854:Up-Regulation
chemical_list: D001549:Benzamides; D053379:Chromogranin A; D050759:Cyclin-Dependent Kinase Inhibitor p21; C121825:N-(5-(3-dimethylaminobenzamido)-2-methylphenyl)-4-hydroxybenzamide; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases