hMTH1 and GPX1 expression in human thyroid tissue is interrelated to prevent oxidative DNA damage

• Published in: DNA repair 2020-11, Vol.95, p.102954, Article 102954
• Main Authors: Arczewska, Katarzyna D., Krasuska, Wanda, Stachurska, Anna, Karpińska, Kamila, Sikorska, Justyna, Kiedrowski, Mirosław, Lange, Dariusz, Stępień, Tomasz, Czarnocka, Barbara
• Format: Article
• Language: English
• Subjects: Cell Line, Tumor; DNA Damage; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Gene Expression Regulation; Glutathione Peroxidase - genetics; Glutathione Peroxidase - metabolism; Glutathione peroxidase 1; Glutathione Peroxidase GPX1; GPX1; hMTH1; Humans; MTH1; NUDT1; Oxidative stress; Oxidative Stress - genetics; Phosphoric Monoester Hydrolases - genetics; Phosphoric Monoester Hydrolases - metabolism; RNA, Messenger - genetics; Thyroid Gland - cytology; Thyroid Gland - metabolism; Thyroid Gland - pathology; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology
• ISSN: 1568-7864; 1568-7856
• DOI: 10.1016/j.dnarep.2020.102954

•hMTH1 depletion downregulates several glutathione-dependent antioxidant defense genes and leads to reduced levels of reactive oxygen species•hMTH1 siRNA-mediated downregulation of antioxidant defense genes sensitizes thyroid cells to glutathione synthesis inhibition•hMTH1 and GPX1 protein and mRNA levels are increased in thyroid tumor tissue.•hMTH1 and GPX1 mRNA levels show strong positive correlation in thyroid tumor and normal tissues. Oxidative stress (OS) is recognized as disturbance of cellular equilibrium between reactive oxygen species (ROS) formation and their elimination by antioxidant defense systems. One example of ROS-mediated damage is generation of potentially mutagenic DNA precursor, 8-oxodGTP. In human cells genomic 8-oxodGTP incorporation is prevented by the MutT homologue 1 (MTH1 or hMTH1 for human MTH1) protein. It is well established that malignant cells, including thyroid cancer cells, require hMTH1 for maintaining proliferation and cancerous transformation phenotype. Above observations led to the development of hMTH1 inhibitors as novel anticancer therapeutics. In the current study we present extensive analysis of oxidative stress responses determining sensitivity to hMTH1 deficiency in cultured thyroid cells. We observe here that hMTH1 depletion results in downregulation of several glutathione-dependent OS defense system factors, including GPX1 and GCLM, making some of the tested thyroid cell lines highly dependent on glutathione levels. This is evidenced by the increased ROS burden and enhanced proliferation defect after combination of hMTH1 siRNA and glutathione synthesis inhibition. Moreover, due to the lack of data on hMTH1 expression in human thyroid tumor specimens we decided to perform detailed analysis of hMTH1 expression in thyroid tumor and peri-tumoral tissues from human patients. Our results allow us to propose here that anticancer activity of hMTH1 suppression may be boosted by combination with agents modulating glutathione pool, but further studies are necessary to precisely identify backgrounds susceptible to such combination treatment.