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

Publication ,  Journal Article
Chatterjee, N; Whitman, MA; Harris, CA; Min, SM; Jonas, O; Lien, EC; Luengo, A; Vander Heiden, MG; Hong, J; Zhou, P; Hemann, MT; Walker, GC
Published in: Proc Natl Acad Sci U S A
November 17, 2020

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

November 17, 2020

Volume

117

Issue

46

Start / End Page

28918 / 28921

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Nucleotidyltransferases
  • Nuclear Proteins
  • Nitroquinolines
  • Neoplasms
  • Mutagenesis
  • Mice
  • Mad2 Proteins
  • Humans
 

Citation

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Chatterjee, N., Whitman, M. A., Harris, C. A., Min, S. M., Jonas, O., Lien, E. C., … Walker, G. C. (2020). REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks. Proc Natl Acad Sci U S A, 117(46), 28918–28921. https://doi.org/10.1073/pnas.2016064117
Chatterjee, Nimrat, Matthew A. Whitman, Cynthia A. Harris, Sophia M. Min, Oliver Jonas, Evan C. Lien, Alba Luengo, et al. “REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.Proc Natl Acad Sci U S A 117, no. 46 (November 17, 2020): 28918–21. https://doi.org/10.1073/pnas.2016064117.
Chatterjee N, Whitman MA, Harris CA, Min SM, Jonas O, Lien EC, et al. REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks. Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28918–21.
Chatterjee, Nimrat, et al. “REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.Proc Natl Acad Sci U S A, vol. 117, no. 46, Nov. 2020, pp. 28918–21. Pubmed, doi:10.1073/pnas.2016064117.
Chatterjee N, Whitman MA, Harris CA, Min SM, Jonas O, Lien EC, Luengo A, Vander Heiden MG, Hong J, Zhou P, Hemann MT, Walker GC. REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks. Proc Natl Acad Sci U S A. 2020 Nov 17;117(46):28918–28921.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

November 17, 2020

Volume

117

Issue

46

Start / End Page

28918 / 28921

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Nucleotidyltransferases
  • Nuclear Proteins
  • Nitroquinolines
  • Neoplasms
  • Mutagenesis
  • Mice
  • Mad2 Proteins
  • Humans