Versatile activity of the master regulator of the antioxidant response in tumor initiation, progression and metastasis

Abstract

Oxidative intermediates derived from endogenous metabolism or xenobiotic stimuli are a major cause of cancer initiation. Host defense systems have evolved to cope with these oxidative stresses and prevent carcinogenesis. The basic leucine zipper transcription factor Nrf2 (Nuclear factor-erythroid derived 2-like 2, Nfe2l2) regulates the cellular defense system against oxidative stress, and governs cellular protection against chemical carcinogens. At the same time, Nrf2 enhances anti-cancer immunity in the tumor microenvironment, thereby suppressing growth and metastasis of cancer cells. These beneficial aspects of Nrf2 activities contribute to the prevention of cancer initiation, as well as its subsequent progression. On the other hand, aberrant Nrf2 activation confers malignant properties on cancer cells by enhancing proliferative ability and drug resistance. Thus, Nrf2 contributes to the prevention of carcinogenesis as well as the malignant growth of cancer cells. Increasing numbers of studies have been focusing on elucidating how these contradictory activities of Nrf2 are elicited during the multistep carcinogenic process. In this research highlight, we discuss our current understandings of Nrf2 function in cancer initiation, promotion and metastasis in a murine lung cancer model, and related topics are summarized.