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

A. Patel, D. G.A. Burton, K. Halvorsen, W. Balkan, T. Reiner, C. Perez-Stable, A. Cohen, A. Munoz, M. G. Giribaldi, S. Singh, D. J. Robbins, D. M. Nguyen, P. Rai

Research output: Contribution to journalArticle

55 Scopus citations

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. In p53-nonfunctional KRAS-mutant cells, MTH1 suppression does not produce DNA damage but reduces proliferation and leads to 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.

Original languageEnglish (US)
Pages (from-to)2586-2596
Number of pages11
JournalOncogene
Volume34
Issue number20
DOIs
StatePublished - May 14 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Patel, A., Burton, D. G. A., Halvorsen, K., Balkan, W., Reiner, T., Perez-Stable, C., Cohen, A., Munoz, A., Giribaldi, M. G., Singh, S., Robbins, D. J., Nguyen, D. M., & Rai, P. (2015). MutT Homolog 1 (MTH1) maintains multiple KRAS-driven pro-malignant pathways. Oncogene, 34(20), 2586-2596. https://doi.org/10.1038/onc.2014.195