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 1

High MTH1 (NUDT1) mRNA is associated with shorter patient survival.

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High MTH1 (NUDT1) mRNA is associated with shorter patient survival. MTH1...
MTH1 inhibition retards mesothelioma progression in vivo. (A) RSEM data of RNA-seq analysis retrieved by the TCGA biobank were analyzed using the UALCAN portal. Kaplan-Meier plot correlating NUDT1 gene expression with mesothelioma patients’ survival (high MTH1, n = 21; low/medium MTH1, n = 64). P value was obtained upon log-rank test. (B–E) Human mesothelioma tumors were created upon s.c. injection of 2 × 106 ZL34 or MSTO-211H cells in NOD.SCID mice. TH1579 administration commenced once tumors became 200 mm3. Mice received vehicle or TH1579 (90 mg/kg body weight) 2 times per day, every 2 days. Tumor size was measured by a digital caliper (B and D). On the day of sacrifice, mesothelioma tumors were excised and weighed (C and E). Data presented as mean ± SEM. ZL34: vehicle and TH1579, n = 17 mice each. MSTO-211: vehicle, n = 6 mice; TH1579, n = 7 mice. *P < 0.05 compared with vehicle by 2-tailed Students’ t test. (F and G) AB1 and AE17 cells were intrapleurally injected into syngeneic BALB/c and C57BL/6 mice, respectively, and animals were treated as above. Fourteen days later, mice were sacrificed and mesothelioma tumors were excised and weighed (F) and pleural fluid was retrieved and quantified (G). Data presented as mean ± SEM. AB1: vehicle, n = 8 mice; TH1579, n = 10 mice. AE17: vehicle, n = 10 mice; TH1579, n = 11 mice. *P < 0.05 compared with vehicle by 2-tailed Students’ t test.