REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks
Nimrat Chatterjee1, Matthew A Whitman2, Cynthia A Harris3
1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; nimrat.chatterjee@med.uvm.edu gwalker@mit.edu.
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.
Insights
Targeting REV1 with JH-RE-06 enhances cisplatin chemotherapy by inducing senescence, not apoptosis. This novel approach alters DNA damage response and boosts cancer cell death.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Translesion synthesis (TLS) via REV1/POLζ aids cell survival post-DNA damage but causes mutations.
- Cisplatin efficacy is enhanced by the REV1 inhibitor JH-RE-06, but the mechanism remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which JH-RE-06 enhances cisplatin efficacy in cancer models.
- To investigate the impact of combined cisplatin/JH-RE-06 treatment on cellular responses to DNA damage.
Main Methods:
- In vitro analysis of human and mouse cell lines.
- In vivo studies using two mouse xenograft models.
- Assessment of senescence markers (e.g., p21, β-galactosidase, Lamin B1), apoptosis, DNA damage foci (p-γ-H2AX), and ATR expression.
Main Results:
- Cisplatin/JH-RE-06 treatment induced senescence hallmarks (p21, β-galactosidase, micronuclei, reduced Lamin B1) and immune regulators (IL6, IL8), leading to cell death, rather than increased apoptosis.
- Combined treatment altered DNA damage signaling, with elevated p-γ-H2AX and reduced ATR expression compared to cisplatin alone.
- REV1 inhibition shifted the cellular response from DNA damage tolerance to senescence and subsequent death.
Conclusions:
- Targeting REV1 with JH-RE-06 profoundly modifies the cellular response to cisplatin, shifting it towards senescence and cell death.
- REV1/POLζ inhibitors represent a promising strategy to enhance the efficacy of DNA-damaging chemotherapy by altering the biological response to genomic damage.
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