title: Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells.
abstract: Galiellalactone (GL) is a fungal metabolite that presents antitumor activities on prostate cancer in vitro and in vivo. In this study we show that GL induced cell cycle arrest in G2/M phase, caspase-dependent apoptosis and also affected the microtubule organization and migration ability in DU145 cells. GL did not induce double strand DNA break but activated the ATR and ATM-mediated DNA damage response (DDR) inducing CHK1, H2AX phosphorylation (fH2AX) and CDC25C downregulation. Inhibition of the ATM/ATR activation with caffeine reverted GL-induced G2/M cell cycle arrest, apoptosis and DNA damage measured by fH2AX. In contrast, UCN-01, a CHK1 inhibitor, prevented GL-induced cell cycle arrest but enhanced apoptosis in DU145 cells. Furthermore, we found that GL did not increase the levels of intracellular ROS, but the antioxidant N-acetylcysteine (NAC) completely prevented the effects of GL on fH2AX, G2/M cell cycle arrest and apoptosis. In contrast to NAC, other antioxidants such as ambroxol and EGCG did not interfere with the activity of GL on cell cycle. GL significantly suppressed DU145 xenograft growth in vivo and induced the expression of fH2AX in the tumors. These findings identify for the first time that GL activates DDR in prostate cancer.
authors.affiliation: Maimónides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: García
authors.affiliation: Maimónides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
authors.forename: Maribel
authors.initials: M
authors.lastname: Lara-Chica
authors.affiliation: Maimónides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Cantarero
authors.affiliation: Department of Science, Centre for Analysis and Synthesis, Lund University, Lund, Sweden.
authors.forename: Olov
authors.initials: O
authors.lastname: Sterner
authors.affiliation: Maimónides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Calzado
authors.affiliation: Maimónides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Córdoba, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D007783:Lactones; C416043:galiellalactone; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM/ATR; CHK1; cancer; cell cycle; galiellalactone