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 language | English |
|---|---|
| Journal | Small GTPases |
| Volume | 3 |
| Issue number | 2 |
| State | Published - Apr 1 2012 |
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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
Human Mut T homolog 1 (MTH1) : A roadblock for the tumor-suppressive effects of oncogenic RAS-induced ROS. / Rai, Priyamvada.
In: Small GTPases, Vol. 3, No. 2, 01.04.2012.Research output: Contribution to journal › Article
}
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 -