MTH1 expression is required for effective transformation by oncogenic HRAS

Maria G. Giribaldi, Anisleidys Munoz, Katherine Halvorsen, Asmita Patel, Priyamvada Rai

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Due to sustaining elevated reactive oxygen species (ROS), oncogenic RAStransformed cells upregulate redox-protective genes, among them the mammalian 8-oxodGTPase, MutT Homolog 1 (MTH1). We previously showed MTH1 abrogates RAS oncogene-induced senescence (OIS) in normal cells and that its inhibition compromises the tumorigenicity of established oncogenic RAS-harboring cancer cells. Here, we investigated how pre-transformation MTH1 levels in immortalized cells influence HRASV12-induced oncogenic transformation. We find MTH1 suppression prior to HRASV12 transduction into BEAS2B immortalized epithelial cells compromised maintenance of high RASV12- and oncogenic ROS-expressing cell populations. Furthermore, pre-transformation MTH1 levels modulated the efficiency of HRASV12-mediated soft agar colony formation. Downstream transformation-associated traits such as the epithelial-mesenchymal transition (EMT) were also compromised by MTH1 inhibition. These collective effects were observed to a greater degree in cells harboring high vs. low RASV12 levels, suggesting MTH1 is required for tumor cells to accumulate RAS oncoprotein. This is significant as, a priori, one cannot ascertain whether tumorpromoting adaptations wrought by introducing oncogenic RAS into an immortalized cell are capable of overcoming pre-transformation deficiencies. Our results suggest nucleotide pool sanitization comprises an important transformation-promoting requirement that, if compromised, cannot be adequately compensated post-transformation and thus is likely to affect optimal development and progression of RAS-driven tumors.

Original languageEnglish (US)
Pages (from-to)11519-11529
Number of pages11
JournalOncotarget
Volume6
Issue number13
DOIs
StatePublished - 2015

Keywords

  • EMT
  • Glycolysis
  • MTH1
  • Oncogenic RAS
  • Transformation

ASJC Scopus subject areas

  • Oncology

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