MTH1 favors mesothelioma progression and mediates paracrine rescue of bystander endothelium from oxidative damage
Sophia F. Magkouta, Apostolos G. Pappas, Photene C. Vaitsi, Panagiotis C. Agioutantis, Ioannis S. Pateras, Charalampos A. Moschos, Marianthi P. Iliopoulou, Chrysavgi N. Kosti, Heleni V. Loutrari, Vassilis G. Gorgoulis, Ioannis T. Kalomenidis
Sophia F. Magkouta, Apostolos G. Pappas, Photene C. Vaitsi, Panagiotis C. Agioutantis, Ioannis S. Pateras, Charalampos A. Moschos, Marianthi P. Iliopoulou, Chrysavgi N. Kosti, Heleni V. Loutrari, Vassilis G. Gorgoulis, Ioannis T. Kalomenidis
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Research Article Angiogenesis Oncology

MTH1 favors mesothelioma progression and mediates paracrine rescue of bystander endothelium from oxidative damage

Abstract

Oxidative stress and inadequate redox homeostasis is crucial for tumor initiation and progression. MTH1 (NUDT1) enzyme prevents incorporation of oxidized dNTPs by sanitizing the deoxynucleoside triphosphate (dNTP) pool and is therefore vital for the survival of tumor cells. MTH1 inhibition has been found to inhibit the growth of several experimental tumors, but its role in mesothelioma progression remained elusive. Moreover, although MTH1 is nonessential to normal cells, its role in survival of host cells in tumor milieu, especially tumor endothelium, is unclear. We validated a clinically relevant MTH1 inhibitor (Karonudib) in mesothelioma treatment using human xenografts and syngeneic murine models. We show that MTH1 inhibition impedes mesothelioma progression and that inherent tumoral MTH1 levels are associated with a tumor’s response. We also identified tumor endothelial cells as selective targets of Karonudib and propose a model of intercellular signaling among tumor cells and bystander tumor endothelium. We finally determined the major biological processes associated with elevated MTH1 gene expression in human mesotheliomas.

Authors

Sophia F. Magkouta, Apostolos G. Pappas, Photene C. Vaitsi, Panagiotis C. Agioutantis, Ioannis S. Pateras, Charalampos A. Moschos, Marianthi P. Iliopoulou, Chrysavgi N. Kosti, Heleni V. Loutrari, Vassilis G. Gorgoulis, Ioannis T. Kalomenidis

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Figure 3

Tumors’ response to Karonudib is associated with intrinsic MTH1 expression levels.

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Tumors’ response to Karonudib is associated with intrinsic MTH1 expressi...
(A) Mth1 mRNA (left) and protein (right) expression levels of murine mesothelioma cells and tumors were determined by real-time PCR and Western blotting, respectively. Data presented as mean ± SEM, n = 3 for each group,*P < 0.05 compared with AB1 by 2-tailed Students’ t test. (B) AB1 cells silenced for MTH1 expression (AB1shmth1) and respective AB1 vector cells (left), or AE17 MTH1–overexpressing cells and respective AE17 vector cells (right), were intrapleurally injected into syngeneic mice and treated as aforementioned. Fourteen days later, mice were sacrificed and mesothelioma tumors were excised and weighed. Data presented as mean ± SEM. AB1, n = 7; AB1+TH1579, n = 6; AB1shmth1, n = 5; AB1shmth1+th1579, n = 5; AE17, n = 11; AE17+TH1579, n = 8; AE17 MTH1–overexpressing (AE17mth1over), n = 7; AE17mth1over+TH1579, n = 6. *P < 0.05 for indicated comparisons by 1-way ANOVA (with Bonferroni’s post hoc test). (C) Tumor’s response to TH1579 inhibitor was evaluated as percent of change of tumor weight referred to respective control group by 2-tailed Students’ t test. Data presented as mean ± SEM, n as in B.*P < 0.05 compared with indicated comparisons. (D and E) Tumor sections of all groups were analyzed for 8-Oxo-dG expression. Data presented as mean ± SEM. AB1, n = 5 for each group; AE17, n = 5 for AE17, AE17+TH157, and AE17mth1over+TH1579 groups; AE17mth1over, n = 7 each. *P < 0.05 compared with indicated comparisons by 1-way ANOVA (with Bonferroni’s post hoc test). (E) Representative pictures of tumor tissue sections stained for 8-Oxo-dG (black arrows). HPF, high power field. Scale bar: 100 μm. Arrows depict positive nuclear staining.