Targeting nrf2 signaling to combat chemoresistance

Abstract

Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that upregulates expression of a battery of genes to combat oxidative and electrophilic stress. Modification of Kelch-like ECH-associated protein 1 (Keap1) by reactive oxygen species stabilizes Nrf2 by escaping from degradation. Nrf2 then binds to antioxidant response elements (AREs) on the promoter region of various genes. Activation of the Keap1-Nrf2-ARE pathway plays critical roles in the chemopreventive effect of various phytochemicals. However, Nrf2 can protect cancer cells from oxidative stress and promote cell proliferation. Moreover, recent studies reveal that activation of the Nrf2 pathway is critical for resistance to chemotherapeutic agents. The aim of this review is to provide a molecular basis for the use of Nrf2 inhibitors in overcoming chemoresistance.

Keywords: Chemotherapy; Inhibitor; Keap1; Nrf2.

Figure 1.

Structures of Kelch-like ECH-associated protein 1 (Keap1) and nuclear factor E2-related factor 2 (Nrf2). BTB, Bric-a-Brac domain; IVR, intervening region; Cul3, Cullin E3 ubiquitin ligase; ROS, reactive oxygen species; DLG and ETGF, binding sites for Keap1.

Figure 2.

The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor E2-related factor 2 (Nrf2)-antioxidant response elements (ARE) signaling pathway. Cul3, Cullin E3 ubiquitin ligase; Ubi, uniquitin; Maf, musculo-aponeurotic fibrosarcoma; HO-1, heme oxygenase-1; NQO1, NAD(P)H: quinone oxidoreductase 1; ABC, ATP binding cassette; MRP, multidrug resistance-associated protein.