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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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
JournalSmall GTPases
Volume3
Issue number2
StatePublished - Apr 1 2012

Fingerprint

Tumors
Reactive Oxygen Species
Epithelial-Mesenchymal Transition
Cell Aging
Neoplasms
Anoikis
DNA
Cell death
Cytotoxicity
Phosphatidylinositol 3-Kinases
Survival
Chemical activation
Cells
DNA Damage
Breast
Cell Death
Up-Regulation
Defects
Epithelial Cells
Maintenance

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

Cite this

@article{3766f890431d4204b688a7558aa55eff,
title = "Human Mut T homolog 1 (MTH1): A roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS",
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.",
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)",
author = "Priyamvada Rai",
year = "2012",
month = "4",
day = "1",
language = "English",
volume = "3",
journal = "Small GTPases",
issn = "2154-1248",
publisher = "Landes Bioscience",
number = "2",

}

TY - JOUR

T1 - Human Mut T homolog 1 (MTH1)

T2 - A roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS

AU - Rai, Priyamvada

PY - 2012/4/1

Y1 - 2012/4/1

N2 - 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.

AB - 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.

KW - 8-oxoguanine (8-oxoG)

KW - Akt activation

KW - DNA damage

KW - E-cadherin

KW - Epithelial-mesenchymal transition (EMT)

KW - MTH1

KW - Oncogene-induced senescence (OIS)

KW - Proliferation

KW - Reactive oxygen species (ROS)

UR - http://www.scopus.com/inward/record.url?scp=84861473820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861473820&partnerID=8YFLogxK

M3 - Article

C2 - 22790201

AN - SCOPUS:84861473820

VL - 3

JO - Small GTPases

JF - Small GTPases

SN - 2154-1248

IS - 2

ER -