Carcinogenesis Advance Access published online on June 12, 2007
Carcinogenesis, doi:10.1093/carcin/bgm128
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Redox Effector Factor-1, Combined with Reactive Oxygen Species, Plays an Important Role in the Transformation of JB6 Cells
Departments of Medicine (Hematology/Oncolgoy Division) and Biological Chemistry, Chao Family Comprehensive Cancer Center, School of Medicine, University of California Irvine 101 The City Drive South, Orange, California 92868
* Address reprint requests to Frank L. Meyskens Jr., M.D., Professor of Medicine and Biology Chemistry, College of Medicine, University of California, Irvine, 101 The City Drive South, Bldg. 56, Room 215, Orange, CA 92868. Phone: (714)456-6310. Fax: (714)456-2240. E-mail: FLMeyske{at}uci.edu
Apurinic/apyrimidinic endonuclease/redox effector factor-1 (APE1/Ref-1) is a multifunctional protein involved both in DNA base excision repair and redox regulation. Studies have suggested that abnormal APE/Ref-1 levels and/or activities are associated with tumor progression and sensitivities to treatment, but no direct evidence has yet been published regarding the role of Ref-1 in malignant transformation. We utilized the well-documented tumor promotor-sensitive JB6 mouse epithelial cell model, as well as new transformants (by UVB, H2O2 or Cadmium) to study this phenomenon.
Significant increases of ROS were observed in JB6P+ and all the transformants compared to promotor-resistant JB6P- cells. These increases were paralleled by a sustained elevation of Ref-1 expression. Further analysis exhibited a strong inverse correlation between oxidative DNA lesions (8-oxo-dG) and Ref-1 levels in all JB6 cells. Notably, apoptosis occurred after knockdown of Ref-1 by siRNA, demonstrated by a 2-fold increase of annexin V-positive JB6P+ cells. Ref-1 depletion also inhibited TPA-induced anchorage-independent growth of JB6P+ by 50% and reduced the colony numbers of JB6P+/H2O2 and JB6P+/Cd cells. Mechanistic studies revealed that Ref-1 reduction was associated with an increase of intracellular ROS levels and a marked decrease of AP-1 transcription activities in JB6P+/H2O2 cells.
This is the first report of the novel role of Ref-1 in cellular transformation. Based on the data presented here, we propose that induction of Ref-1, serving as an adaptive response to elevated ROS, plays a critical role in transformation and protects cells from excess ROS stresses through both DNA repair and activation of transcription factors such as AP-1.
Key Words: ROS • Ref-1/APE • JB6P cells • transformation • UVB
Received February 6, 2007; revised April 13, 2007; accepted May 17, 2007.
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