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The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment

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Abstract

Nrf2 acts as a sensor of oxidative or electrophilic stress and prevents genome instability. The activation of Nrf2 signaling induces ARE-dependent expression of detoxifying and antioxidant defense proteins. Nrf2-ARE signaling has become an attractive target for cancer chemoprevention. On the other hand, constitutive over-activation of Nrf2 in cancer cells has been implicated in cancer progression as well as in resistance to cancer chemotherapeutics.

Two basic Nrf2 activation pathways were described. The canonical pathway is the primary mechanism of Nrf2 activation and is based on dissociation of Nrf2 from its inactive complex with the repressor protein Keap1 and the subsequent translocation of Nrf2 into the nucleus. Numerous proteins which compete with Nrf2 for Keap1 binding stabilize Nrf2 and are involved in non-canonical pathways of Nrf2 activation.

However, growing evidence indicates that the regulation of Keap1-Nrf2-ARE is more complex than was previously thought and that other molecular mechanisms are also involved. Among them is epigenetic regulation of Nrf2 and Keap1, which seems to be a particularly interesting subject for future studies. Nrf2 has become an important chemopreventive and therapeutic target, and many natural and synthetic chemicals have been described as its modulators. However, most small molecules which are either inducers or inhibitors of Nrf2 may provoke “off-target” toxic effects because of their electrophilic character.

This review highlights Nrf2-ARE activation pathways and their role in cancer prevention and therapy. A critical evaluation of currently available Nrf2 inducers and inhibitors is also presented.

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Abbreviations

ARE:

antioxidant response element

ATRA:

all-trans-retinoic acid

bZip:

basic leucine zipper

CBP:

CREB-binding protein

CNC:

cap ‘n’ collar

ERK:

extracellular signal-regulated kinase

HO-1:

heme oxygenase-1

JNK:

c-Jun-NH2-terminal kinase

Keap1:

Kelch-like ECH-associated protein 1

Maf:

musculo-aponeurotic fibrosarcoma protein

miRs:

microRNAs

Nrf2:

NF-E2-nuclear factor erythroid-derived 2

NLS:

nuclear localization signal

PERK:

PKR-like endoplasmic reticulum-resident kinase

PKC:

protein kinase C

β-TrCP:

β-transducin repeat-containing protein

SNP:

single nucleotide polymorphism

UPS:

ubiquitin proteasome system

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  1. Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznań, Poland

    Violetta Krajka-Kuźniak, Jarosław Paluszczak & Wanda Baer-Dubowska

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  1. Violetta Krajka-Kuźniak
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  2. Jarosław Paluszczak
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Krajka-Kuźniak, V., Paluszczak, J. & Baer-Dubowska, W. The Nrf2-ARE signaling pathway: An update on its regulation and possible role in cancer prevention and treatment. Pharmacol. Rep 69, 393–402 (2017). https://doi.org/10.1016/j.pharep.2016.12.011

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