Cytoprotection "gone astray": Nrf2 and its role in cancer

Abstract

Nrf2 has gained great attention with respect to its pivotal role in cell and tissue protection. Primarily defending cells against metabolic, xenobiotic and oxidative stress, Nrf2 is essential for maintaining tissue integrity. Owing to these functions, Nrf2 is regarded as a promising drug target in the chemoprevention of diseases, including cancer. However, much evidence has accumulated that the beneficial role of Nrf2 in cancer prevention essentially depends on the tight control of its activity. In fact, the deregulation of Nrf2 is a critical determinant in oncogenesis and found in many types of cancer. Therefore, amplified Nrf2 activity has profound effects on the phenotype of tumor cells, including radio/chemoresistance, apoptosis protection, invasiveness, antisenescence, autophagy deficiency, and angiogenicity. The deregulation of Nrf2 can result from various epigenetic and genetic alterations directly affecting Nrf2 control or from the complex interplay of Nrf2 with numerous oncogenic signaling pathways. Additionally, alterations of the cellular environment, eg, during inflammation, contribute to Nrf2 deregulation and its persistent activation. Therefore, the status of Nrf2 as anti- or protumorigenic is defined by many different modalities. A better understanding of these modalities is essential for the safe use of Nrf2 as an activation target for chemoprevention on the one hand and as an inhibition target in cancer therapy on the other. The present review mainly addresses the conditions that promote the oncogenic function of Nrf2 and the resulting consequences providing the rationale for using Nrf2 as a target structure in cancer therapy.

Keywords: cancer therapy; carcinogen; transcription factor; tumorigenesis; xenobiotic and oxidative stress.

Figure 1

(A and B) Principle of controlling Nrf2 by Keap1 and its activation. Notes: (A) Under homeostatic conditions, Nrf2 is kept at low levels through its Keap1-dependent targeting to Cullin3/Rbx1-mediated Lys-48 polyubiquitination and subsequent proteasomal degradation. (B) During exposure to stress activators, the interaction between Nrf2 and Keap1 is weakened, thereby impairing Nrf2 polyubiquitination. While free Nrf2 then can enter the nucleus and drive antioxidant response element (ARE)-dependent gene expression along with certain modifications (eg, Ser-40 phosphorylation, acetylation), Keap-1 can be subject to Lys-63 polyubiquitination that leads to the release of Nrf2. Ubiquitin-specific protease (USP)-15 deubiquitinase reverses Keap1 polyubiquitination.

Figure 2

Interaction of Nrf2 and Keap1 according to the hinge–latch model. Notes: Nrf2 tightly binds to homodimeric Keap1 through interaction of the ETGE and DLG motifs within the Neh2 domain and either one of the double-glycine repeat (DGR) sites of Keap1. This configuration facilitates polyubiquitination of Nrf2 by Cullin3/Rbx1. Upon sulfhydryl modifications of certain cysteine residues of Keap1, the DLG motif of Nrf2 is released from the interaction with the DGR site. This blocks polyubiquitination of Nrf2, which however remains bound to the Keap1 dimer through the ETGE/DGR interaction. Thereby, Keap1 is saturated with Nrf2 leaving yet-unbound Nrf2 free and capable of entering the nucleus. Abbreviations: DNA, deoxyribonucleic acid; BTB, bric-a-brac; IVR, intervening region.

Figure 3

The dual role of Nrf2 in cancer. Notes: As long as it is kept under homeostatic control, Nrf2 activation protects cellular components like DNA from damaging insults arising from acute/temporary oxidative and xenobiotic stress. In this way, Nrf2 prevents tumor development. When deregulated by 1) epigenetic and genetic alterations affecting the Keap1–Nrf2 pathway, 2) persistent stress conditions, and/or 3) oncogenic pathways, Nrf2 activation facilitates the growth and survival of transformed cells, thus promoting tumorigenesis. Abbreviations: ROS, reactive oxygen species; DNA, deoxyribonucleic acid; tBHQ, tert-butylhydroquinone; SFN, sulforaphane.