REV1 Inhibition Enhances Radioresistance and Autophagy

Cancers

Pei Zhou¹  Won Y. Lim²  Jiyong Hong²  Nimrat Chatterjee³  Kanayo E. Ikeh³  Erica N. Lamkin³  Andrew Crompton³  Kira J. Fisher³  Jamie Deutsch³  Dmitry M. Korzhnev⁴  M. Kyle Hadden⁵  David J. Argyle⁶  Mark Gray⁶ 

[1] Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710, USA;Department of Chemistry, Duke University, Durham, NC 27708, USA;Department of Microbiology and Molecular Genetics, University of Vermont, Burlington, VT 05405, USA;Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030, USA;Department of Pharmaceutical Sciences, University of Connecticut, 69 N Eagleville Rd, Unit 3092, Storrs, CT 06269-3092, USA;The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, Roslin, Midlothian, Edinburgh EH25 9RG, UK;

关键词: translesion synthesis;    radioresistance;    autophagy;    REV1;    ionizing radiations;    etoposide;   

DOI  :  10.3390/cancers13215290

来源: DOAJ

【 摘 要 】

Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens.

【 授权许可】

Unknown