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Overexpressed c-Myc Sensitizes Cells to TH1579, a Mitotic Arrest and Oxidative DNA Damage Inducer

Affiliation
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, 17165 Stockholm, Sweden
Henriksson, Sofia;
ORCID
0000-0001-6845-797X
Affiliation
Department of Pharmacology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain
Calderón-Montaño, José Manuel;
ORCID
0000-0003-4529-667X
Affiliation
Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, 97070 Würzburg, Germany
Solvie, Daniel;
ORCID
0000-0002-6372-1396
Affiliation
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, 17165 Stockholm, Sweden
Warpman Berglund, Ulrika;
ORCID
0000-0002-7384-092X
Affiliation
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institute, 17165 Stockholm, Sweden
Helleday, Thomas

Previously, we reported that MTH1 inhibitors TH588 and TH1579 selectively induce oxidative damage and kill Ras-expressing or -transforming cancer cells, as compared to non-transforming immortalized or primary cells. While this explains the impressive anti-cancer properties of the compounds, the molecular mechanism remains elusive. Several oncogenes induce replication stress, resulting in under replicated DNA and replication continuing into mitosis, where TH588 and TH1579 treatment causes toxicity and incorporation of oxidative damage. Hence, we hypothesized that oncogene-induced replication stress explains the cancer selectivity. To test this, we overexpressed c-Myc in human epithelial kidney cells (HA1EB), resulting in increased proliferation, polyploidy and replication stress. TH588 and TH1579 selectively kill c-Myc overexpressing clones, enforcing the cancer cell selective killing of these compounds. Moreover, the toxicity of TH588 and TH1579 in c-Myc overexpressing cells is rescued by transcription, proteasome or CDK1 inhibitors, but not by nucleoside supplementation. We conclude that the molecular toxicological mechanisms of how TH588 and TH1579 kill c-Myc overexpressing cells have several components and involve MTH1-independent proteasomal degradation of c-Myc itself, c-Myc-driven transcription and CDK activation.

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