MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways.

摘要: Oncogenic RAS promotes production of reactive oxygen species (ROS), which mediate pro-malignant signaling but can also trigger DNA damage-induced tumor suppression. Thus RAS-driven cells require redox-protective mechanisms to mitigate the damaging aspects ROS. Here, we show that MutT Homolog 1 (MTH1), mammalian 8-oxodGTPase sanitizes oxidative damage in nucleotide pool, is important for maintaining several KRAS-driven traits a nonsmall cell lung carcinoma (NSCLC) model. MTH1 suppression KRAS-mutant NSCLC impairs proliferation and xenograft formation. Furthermore, levels modulate KRAS-induced transformation immortalized epithelial cells. expression upregulated by oncogenic KRAS correlates positively with high human tumors. At molecular level, p53-competent cells, loss provokes induction oncogene-induced senescence. In p53-nonfunctional does not produce reduces leads an adaptive decrease levels. Thus, only enables evasion its consequences, function as rheostat oncogene at optimal Accordingly, our results indicate novel critical component KRAS-associated malignancy inhibition likely yield significant tumor-suppressive outcomes