Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis

DeNicola, G.M. et al. 2011. Nature 475, 106-109

Speaker：Fang-Hsin Chang (張芳馨)                           Time：13:10~16:00, Sep. 28 2011

Commentator：Dr. Cheng-Chan Lu (呂政展老師)      Place：Room 601

Abstract：

        High levels of reactive oxygen species (ROS) have been considered to promote tumor progression [1]. Recent studies, however, showed that the level of Nrf2, a transcription factor promoting antioxidant pathways, was increased in some cancers. Moreover, gene mutations that cause Nrf2 stabilization and thus protect cells against oxidative stress have also been detected in subsets of human cancers derived from lung, head-and-neck, and gallbladder [2]. Therefore, this study is aimed to examine regulation and function of Nrf2 and its downstream antioxidant program intumorigenesis. In contrast to previous reports that ectopic overexpression of oncogenes increased ROS production, the authors found that physiological expression of endogenous oncogenic K-Ras^G12D and Myc^ERT2 lowered ROS production. Further investigation showed that endogenous expression of the oncogenes reduced the ROS level through upregulating Nrf2 and its downstream antioxidant genes. The oncogene-induced upregulation of Nrf2 was mediated by the Raf-MEK-ERK-Jun pathway. Importantly, the authors presented evidence that the Nrf2-induced antioxidant program was elevated in the early stages of K-Ras-driven development of pancreatic cancer in vivo. Nrf2 deficiency resulted in significant reduction in tumor burden and cell proliferation, and also an increase of survival. In conclusion, this study reveals a new mechanism of oncogene-directed activation of the Nrf2 antioxidant program and suggests that detoxification of ROS is also required for tumorigenesis. As for clinical application, ablation of the protective antioxidant pathway to make cancer cells more vulnerable to oxidative stress may be of therapeutic value.

References：

1.         Irani, K., et al., Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science, 1997. 275(5306): p. 1649-52.

2.         Hayes, J.D. and M. McMahon, NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci, 2009. 34(4): p. 176-88.