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MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways
- Source :
- Oncogene
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
Abstract
- 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 tumor cells require redox-protective mechanisms to mitigate the damaging aspects of ROS. Here we show that MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase that sanitizes oxidative damage in the nucleotide pool, is important for maintaining several KRAS-driven pro-malignant traits in a nonsmall cell lung carcinoma (NSCLC) model. MTH1 suppression in KRAS-mutant NSCLC cells impairs proliferation and xenograft tumor formation. Furthermore, MTH1 levels modulate KRAS-induced transformation of immortalized lung epithelial cells. MTH1 expression is upregulated by oncogenic KRAS and correlates positively with high KRAS levels in NSCLC human tumors. At a molecular level, in p53-competent KRAS-mutant cells, MTH1 loss provokes DNA damage and induction of oncogene-induced senescence (OIS). In p53-nonfunctional KRAS-mutant cells, MTH1 suppression does not produce DNA damage but induces a reduced proliferative rate and an adaptive decrease in KRAS expression levels. Thus, MTH1 not only enables evasion of oxidative DNA damage and its consequences but can also function as a molecular rheostat for maintaining oncogene expression at optimal levels. Accordingly, our results indicate MTH1 is a novel and critical component of oncogenic KRAS-associated malignancy and its inhibition is likely to yield significant tumor-suppressive outcomes in KRAS-driven tumors.
- Subjects :
- p53
Male
Senescence
Cancer Research
Lung Neoplasms
DNA damage
DNA repair
Cell
Mice, Nude
Biology
reactive oxygen species (ROS)
medicine.disease_cause
Article
Nonsmall cell lung carcinoma
Proto-Oncogene Proteins p21(ras)
Mice
Carcinoma, Non-Small-Cell Lung
Proto-Oncogene Proteins
Genetics
medicine
Animals
Humans
neoplasms
Molecular Biology
Cell Proliferation
Regulation of gene expression
nucleotide pool
Oncogene
Cell growth
transformation
Phosphoric Monoester Hydrolases
digestive system diseases
Up-Regulation
respiratory tract diseases
Cell biology
Gene Expression Regulation, Neoplastic
DNA Repair Enzymes
medicine.anatomical_structure
ras Proteins
Female
KRAS
Tumor Suppressor Protein p53
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....b1bf63d447b718ad4854955f56c95e69