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Title: Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells.
Authors: García, Víctor
Lara-Chica, Maribel
Cantarero, Irene
Sterner, Olov
Calzado, Marco A
Muñoz, Eduardo
Keywords: ATM/ATR;CHK1;cancer;cell cycle;galiellalactone
metadata.dc.subject.mesh: Animals
Ataxia Telangiectasia Mutated Proteins
Blotting, Western
Cell Cycle Checkpoints
Cell Movement
Cell Proliferation
Comet Assay
DNA Damage
Fluorescent Antibody Technique
Immunoenzyme Techniques
Mice, Nude
Prostatic Neoplasms
Tumor Cells, Cultured
Wound Healing
Xenograft Model Antitumor Assays
Issue Date: 2016
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.
metadata.dc.identifier.doi: 10.18632/oncotarget.6606
Appears in Collections:Producción 2020

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