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 4

MTH1 is overexpressed by tumor endothelium, and tumor endothelial cells are selectively targeted by Karonudib.

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MTH1 is overexpressed by tumor endothelium, and tumor endothelial cells ...
Endothelial cells of MTH1-overexpressing tumors are more sensitive to MTH1 inhibition. (A) Endothelial cells from AB1, AE17, and AE17 MTH1–overexpressing tumors (TECs) and normal endothelial cells (NECs) from lung tissue were isolated, and mRNA levels of Mth1 was quantified by real-time PCR. Data are presented as mean ± SEM, n = 3 for each group. *P < 0.05 compared with NECs by 2-tailed Students’ t test. (B) Endothelial cells of AB1, AE17, and AE17 MTH1–overexpressing tumors from mice treated with vehicle or TH1579 were isolated using magnetic beads bearing anti-CD31 antibody. TECs were fixed, permeabilized, and stained for caspase-3 in order to measure apoptotic cells using flow cytometry. Data are presented as mean ± SEM, n = 3 for each vehicle and n = 4 for each TH1579 group. *P < 0.05 compared with indicated groups by 2-tailed Students’ t test. (C) Isolated TECs and NECs from AB1, AE17, and AE17 MTH1–overexpressing mesotheliomas were seeded at 6 × 103 cells/well in 96-well plates and subsequently treated with escalating doses of TH1579 (1–1000 μM). Cell viability was determined by XTT reduction. Data are presented as mean ± SEM, n = 6 for each group. *P < 0.05 compared with vehicle by 2-tailed Students’ t test. #P < 0.05 compared with TECs by 2-tailed Students’ t test. (D) Alternatively, the aforementioned isolated TECs and NECs were serum starved for 4 hours and challenged to migrate toward full medium. Data are presented as mean ± SEM. n = 3 for both groups of AB1 and AE17 NECs, AE17 TECs, AE17 MTH1–overexpressing (AE17mth1over) TECs; n = 4 for each group of AB1 TECs. *P < 0.05 compared with indicated groups by 2-tailed Students’ t test. (E) The aforementioned isolated TECs and NECs were challenged to form capillary-like tubes de novo on Matrigel. Data are presented as mean ± SEM, n = 3 for both groups of AB1 NECs, n = 5 for both groups of AE17 NEC and AE17mth1over TECs, n = 4 for each group of AB1 and AE17 TECs. *P < 0.05 compared with indicated groups by 2-tailed Students’ t test.