title: Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition.
abstract: Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity. Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1α response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance. Cancer Res; 76(8); 2366-75. ©2016 AACR.
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. lars.brautigam@scilifelab.se thomas.helleday@scilifelab.se.
authors: Lars
authors: L
authors: Bräutigam
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Linda
authors: L
authors: Pudelko
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Ann-Sofie
authors: AS
authors: Jemth
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Helge
authors: H
authors: Gad
authors: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors: Mohit
authors: M
authors: Narwal
authors: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors: Robert
authors: R
authors: Gustafsson
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Stella
authors: S
authors: Karsten
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Jordi
authors: J
authors: Carreras Puigvert
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Evert
authors: E
authors: Homan
authors: Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Life Science Center, Düsseldorf, Germany.
authors: Carsten
authors: C
authors: Berndt
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: Ulrika Warpman
authors: UW
authors: Berglund
authors: Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors: Pål
authors: P
authors: Stenmark
authors: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. lars.brautigam@scilifelab.se thomas.helleday@scilifelab.se.
authors: Thomas
authors: T
authors: Helleday
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors*; D006801:Humans; D010084:Oxidation-Reduction; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D059016:Tumor Microenvironment; D015027:Zebrafish
chemical_list: D010744:Phosphoric Monoester Hydrolases; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes