REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.
REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis. Rather, it increases hallmarks of senescence such as senescence-associated β-galactosidase, increased p21 expression, micronuclei formation, reduced Lamin B1, and increased expression of the immune regulators IL6 and IL8 followed by cell death. Moreover, although p-γ-H2AX foci formation was elevated and ATR expression was low in single agent cisplatin-treated cells, the opposite was true in cells treated with cisplatin/JH-RE-06. These observations suggest that targeting REV1 with JH-RE-06 profoundly affects the nature of the persistent genomic damage after cisplatin treatment and also the resulting physiological responses. These data highlight the potential of REV1/POLζ inhibitors to alter the biological response to DNA-damaging chemotherapy and enhance the efficacy of chemotherapy.
['Chatterjee|Nimrat|N|0000-0001-6556-9423', 'Whitman|Matthew A|MA|0000-0002-5399-5318', 'Harris|Cynthia A|CA|0000-0002-2530-5519', 'Min|Sophia M|SM|0000-0001-9840-2996', 'Jonas|Oliver|O|0000-0003-2512-2007', 'Lien|Evan C|EC|0000-0001-7866-4761', 'Luengo|Alba|A|0000-0002-4236-0229', 'Vander Heiden|Matthew G|MG|0000-0002-6702-4192', 'Hong|Jiyong|J|0000-0002-5253-0949', 'Zhou|Pei|P|0000-0002-7823-3416', 'Hemann|Michael T|MT|0000-0001-6776-2163', 'Walker|Graham C|GC|0000-0001-7243-8261']
D000375:Aging D000818:Animals D000971:Antineoplastic Combined Chemotherapy Protocols D045744:Cell Line, Tumor D002945:Cisplatin D004247:DNA D004249:DNA Damage D004260:DNA Repair D004261:DNA Replication D004259:DNA-Directed DNA Polymerase D019008:Drug Resistance, Neoplasm D004357:Drug Synergism D004791:Enzyme Inhibitors D006801:Humans D064246:Mad2 Proteins D051379:Mice D016296:Mutagenesis D009369:Neoplasms D009600:Nitroquinolines D009687:Nuclear Proteins D009713:Nucleotidyltransferases D014407:Tumor Cells, Cultured D023041:Xenograft Model Antitumor Assays
Rev1 chemotherapy senescence translesion synthesis cell death