title: Induction of DNA damage and ATF3 by retigeric acid B, a novel topoisomerase II inhibitor, promotes apoptosis in prostate cancer cells.
abstract: Retigeric acid B (RB) has been reported to exhibit its anti-tumor activity in vitro and in vivo. Here, we found that RB significantly inhibited activity of topoisomerase IIα (Topo IIα), leading to remarkable DNA damage in prostate cancer (PCa) cells as evidenced by a strong induction of γH2AX and DNA fragmentation. Activation of ATM and ATR sequentially led to induction of phospho-Chk1/2 and phospho-Cdc25 in response to RB. Blockade of ATM/ATR signaling resulted in the attenuation of RB-induced γH2AX, and partially rescued RB-mediated cell death. RB treatment also resulted in inactivation of DNA repair proteins such as phospho-BRCA1, impairment of HR, and NHEJ repair as indicated by DNA end-joining assays. Meanwhile, a stress-responsive gene activating transcription factor 3 (ATF3) was noted for its predominant expression in response to RB-induced DNA damage. Knockdown of ATF3 inhibited the RB-induced expression changes of cell cycle- and apoptosis-related genes such as DR5, DDIT4, CDC25A, GADD45A, and partially blocked RB-mediated inhibition on cell proliferation and induction of apoptosis, suggesting the crucial involvement of ATF3 in this event. Microarray data displayed that RB caused changes of genes required for damaged-DNA binding and repair, as well as ATF3 and its target genes. Our data firstly demonstrated that RB was a novel DNA Topo II inhibitor and triggered cell death by inducing DNA damage and stress-response, suggesting a promising anticancer agent.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan 250012, China.
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Fengbin
authors.initials: F
authors.lastname: Gao
authors.forename: Hanming
authors.initials: H
authors.lastname: Jiang
authors.forename: Leilei
authors.initials: L
authors.lastname: Niu
authors.forename: Yiling
authors.initials: Y
authors.lastname: Bi
authors.forename: Charles Y F
authors.initials: CY
authors.lastname: Young
authors.forename: Huiqing
authors.initials: H
authors.lastname: Yuan
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
mesh_terms: D051700:Activating Transcription Factor 3 / Q000502:physiology*; D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D059005:Topoisomerase II Inhibitors; D014315:Triterpenes; D025521:Tumor Suppressor Proteins; C540615:retigeric acid B; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases
keywords: ATF3; DNA damage response; Retigeric acid B; Topoisomerase IIα