Human Mut T homolog 1 (MTH1): A roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS

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26 Scopus citations

Abstract

Oncogenic RAS-induced reactive oxygen species (ROS) trigger barriers to cell transformation and cancer progression through tumor-suppressive responses such as cellular senescence or cell death. We have recently shown that oncogenic RAS-induced DNA damage and attendant premature senescence can be prevented by overexpressing human MutT Homolog 1 (MTH1), the major mammalian detoxifier of the oxidized DNA precursor, 8-oxo-dGTP. Paradoxically, RAS-induced ROS are also able to participate in tumor progression via transformative processes such as mitogenic signaling, the epithelial-mesenchymal transition (EMT), anoikis inhibition and PI3K/Akt-mediated survival signaling. Here we provide a preliminary insight into the influence of MTH1 levels on the EMT phenotype and Akt activation in RAS-transformed HMLE breast epithelial cells. Within this context, we will discuss the implications of MTH1 upregulation in oncogenic RAS-sustaining cells as a beneficial adaptive change that inhibits ROS-mediated cell senescence and participates in the maintenance of ROS-associated tumor-promoting mechanisms. Accordingly, targeting MTH1 in RAS-transformed tumor cells will not only induce proliferative defects but also potentially enhance therapeutic cytotoxicity by shifting cellular response away from pro-survival mechanisms.

Original languageEnglish (US)
Number of pages1
JournalSmall GTPases
Volume3
Issue number2
StatePublished - Jan 1 2012

Keywords

  • 8-oxoguanine (8-oxoG)
  • Akt activation
  • DNA damage
  • E-cadherin
  • Epithelial-mesenchymal transition (EMT)
  • MTH1
  • Oncogene-induced senescence (OIS)
  • Proliferation
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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