title: Inhibition of poly(ADP-ribose) polymerase (PARP) and ataxia telangiectasia mutated (ATM) on the chemosensitivity of mantle cell lymphoma to agents that induce DNA strand breaks.
abstract: There is a high incidence of genomic aberration of ataxia telangiectasia mutated (ATM) and genes encoding proteins involved in the ATM pathway in mantle cell lymphoma (MCL). It has been shown that poly(ADP-ribose) polymerase inhibitor (PARPi) strongly enhances the cytotoxicity of agents, causing single-strand DNA breaks in cells with impaired homologous recombination repair. Here, we show that PARPi AG14361 potentiates the cytotoxicity induced by topotecan treatment in MCL cell lines, which was not dependent on either TP53 or CHEK2 status. Inhibition and/or knockdown of ATM and BRCA2 did not potentiate the cytotoxic effect of treatment with PARPi and topotecan. With loss of function of ATM, other kinases can still mediate activation of ATM substrates as demonstrated by continued phosphorylation of CHEK2 (Thr-68), although attenuated and delayed. These results suggest that PARPi may enhance the therapeutic efficacy of DNA damaging agents on MCL through TP53-independent mechanisms without requiring the inhibition of either ATM or BRCA2.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Radha M
authors.initials: RM
authors.lastname: Golla
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Yulei
authors.initials: Y
authors.lastname: Shen
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.forename: Ying
authors.initials: Y
authors.lastname: Yan
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Greiner
authors.forename: Timothy W
authors.initials: TW
authors.lastname: McKeithan
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects* / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005720:Gamma Rays; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology; D019772:Topotecan / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019772:Topotecan; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases