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Increased ROS levels contribute to elevated transcription factor and MAP kinase activities in malignantly progressed
A Gupta1, S F Rosenberger, G T Bowden
1Department of Radiation Oncology, The University of Arizona Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724, USA.
Abstract:
There is evidence that reactive oxygen species (ROS) are important mediators of tumor promotion and progression. The molecular mechanisms involved in ROS-mediated signaling, however, are unclear at present. Using ionizing radiation and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as model physical and chemical carcinogens, we have malignantly progressed 308 cells, a papilloma-producing mouse keratinocyte cell line, and investigated the molecular alterations in the progressed phenotypes. In this study, we demonstrate that both MNNG and radiation-progressed malignant variants showed elevated ROS levels that contributed to their proliferative capacity in vitro as well as in vivo. We found increased Erk-1/2 and p38 MAP kinase activities to be important components of ROS-mediated signaling. The pro-oxidant state also contributed to constitutive elevation of AP-1, NFkappaB and cAMP response element transactivation in the malignant phenotype. Our data provide evidence for a functional role of elevated ROS levels in tumor progression and implicate Erk-1/2 and p38 MAP kinase activation in the malignant progression of mouse keratinocytes.
Insights
Elevated reactive oxygen species (ROS) drive tumor progression by activating key signaling pathways like Erk-1/2 and p38 MAP kinase. This study reveals ROS
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Reactive oxygen species (ROS) are implicated in tumor promotion and progression.
- The precise molecular mechanisms of ROS-mediated signaling in cancer remain largely undefined.
Purpose of the Study:
- To investigate the role of elevated ROS levels in malignant progression of mouse keratinocytes.
- To elucidate the molecular signaling pathways activated by ROS during tumor progression.
Main Methods:
- Malignant progression of 308 mouse keratinocyte cell line using ionizing radiation and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG).
- Quantification of ROS levels in progressed malignant variants.
- Analysis of Erk-1/2, p38 MAP kinase, AP-1, NFkappaB, and cAMP response element transactivation.
Main Results:
- Malignant variants exhibited elevated ROS levels, contributing to both in vitro and in vivo proliferation.
- Increased Erk-1/2 and p38 MAP kinase activities were identified as crucial components of ROS signaling.
- A pro-oxidant state correlated with constitutive elevation of AP-1, NFkappaB, and cAMP response element transactivation.
Conclusions:
- Elevated ROS levels play a functional role in the malignant progression of mouse keratinocytes.
- Erk-1/2 and p38 MAP kinase activation are implicated in ROS-driven tumor progression.