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Publication Detail

Title: REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.

Authors: Chatterjee, Nimrat; Whitman, Matthew A; Harris, Cynthia A; Min, Sophia M; Jonas, Oliver; Lien, Evan C; Luengo, Alba; Vander Heiden, Matthew G; Hong, Jiyong; Zhou, Pei; Hemann, Michael T; Walker, Graham C

Published In Proc Natl Acad Sci U S A, (2020 11 17)

Abstract: 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.

PubMed ID: 33168727 Exiting the NIEHS site

MeSH Terms: Aging/drug effects; Aging/pathology; Aging/physiology; Animals; Antineoplastic Combined Chemotherapy Protocols/pharmacology*; Cell Line, Tumor; Cisplatin/administration & dosage; Cisplatin/pharmacology; DNA Damage/physiology; DNA Repair; DNA Replication; DNA-Directed DNA Polymerase/metabolism; DNA/biosynthesis; Drug Resistance, Neoplasm; Drug Synergism; Enzyme Inhibitors/administration & dosage; Enzyme Inhibitors/pharmacology*; Humans; Mad2 Proteins/metabolism; Mice; Mutagenesis; Neoplasms/drug therapy*; Neoplasms/enzymology; Neoplasms/pathology; Nitroquinolines/pharmacology*; Nuclear Proteins/metabolism; Nucleotidyltransferases/antagonists & inhibitors*; Nucleotidyltransferases/metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays/methods

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