Targeting Nrf2 Signaling to Combat Chemoresistance

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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.

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Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution.

Keiko Taguchi, Hozumi Motohashi, Masayuki Yamamoto (2011)

The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.

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Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2.

Xiao-Jun Wang, Zheng Sun, Nicole F Villeneuve … (2008)

Drug resistance during chemotherapy is the major obstacle to the successful treatment of many cancers. Here, we report that inhibition of NF-E2-related factor 2 (Nrf2) may be a promising strategy to combat chemoresistance. Nrf2 is a critical transcription factor regulating a cellular protective response that defends cells against toxic insults from a broad spectrum of chemicals. Under normal conditions, the low constitutive amount of Nrf2 protein is maintained by the Kelch-like ECH-associated protein1 (Keap1)-mediated ubiquitination and proteasomal degradation system. Upon activation, this Keap1-dependent Nrf2 degradation mechanism is quickly inactivated, resulting in accumulation and activation of the antioxidant response element (ARE)-dependent cytoprotective genes. Since its discovery, Nrf2 has been viewed as a 'good' transcription factor that protects us from many diseases. In this study, we demonstrate the dark side of Nrf2: stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin and etoposide. Inversely, downregulation of the Nrf2-dependent response by overexpression of Keap1 or transient transfection of Nrf2-small interfering RNA (siRNA) rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical tert-butylhydroquinone (tBHQ) also enhanced the resistance of cancer cells, indicating the feasibility of using small chemical inhibitors of Nrf2 as adjuvants to chemotherapy to increase the efficacy of chemotherapeutic agents. Furthermore, we provide evidence that the strategy of using Nrf2 inhibitors to increase efficacy of chemotherapeutic agents is not limited to certain cancer types or anticancer drugs and thus can be applied during the course of chemotherapy to treat many cancer types.

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Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism.

Dongmei Ren, Nicole F Villeneuve, Tao Jiang … (2011)

The major obstacle in cancer treatment is the resistance of cancer cells to therapies. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive for cancer cell survival. Here, we report the identification of brusatol as a unique inhibitor of the Nrf2 pathway that sensitizes a broad spectrum of cancer cells and A549 xenografts to cisplatin and other chemotherapeutic drugs. Mechanistically, brusatol selectively reduces the protein level of Nrf2 through enhanced ubiquitination and degradation of Nrf2. Consequently, expression of Nrf2-downstream genes is reduced and the Nrf2-dependent protective response is suppressed. In A549 xenografts, brusatol and cisplatin cotreatment induced apoptosis, reduced cell proliferation, and inhibited tumor growth more substantially when compared with cisplatin treatment alone. Additionally, A549-K xenografts, in which Nrf2 is expressed at very low levels due to ectopic expression of Keap1, do not respond to brusatol treatment, demonstrating that brusatol-mediated sensitization to cisplatin is Nrf2 dependent. Moreover, a decrease in drug detoxification and impairment in drug removal may be the primary mechanisms by which brusatol enhances the efficacy of chemotherapeutic drugs. Taken together, these results clearly demonstrate the effectiveness of using brusatol to combat chemoresistance and suggest that brusatol can be developed into an adjuvant chemotherapeutic drug.

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Author and article information

Journal

Journal ID (nlm-ta): J Cancer Prev

Journal ID (iso-abbrev): J Cancer Prev

Journal ID (publisher-id): JCP

Title: Journal of Cancer Prevention

Publisher: Korean Society of Cancer Prevention

ISSN (Print): 2288-3649

ISSN (Electronic): 2288-3657

Publication date (Print): June 2014

Volume: 19

Issue: 2

Pages: 111-117

Affiliations

[1 ]Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital, Seongnam, Korea

[2 ]Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea

[3 ]Cancer Research Institute, Seoul National University, Seoul, Korea

[4 ]Major in Biomodulation, World Class University, Seoul National University, Seoul, Korea

Author notes

Correspondence to: Yong Sang Song, Department of Obstetrics and Gynecology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea, Tel: +82-2-2072-2822, Fax: +82-2-762-3599, E-mail: yssong@ 123456snu.ac.kr

Article

Publisher ID: jcp-19-111

DOI: 10.15430/JCP.2014.19.2.111

PMC ID: 4204167

PubMed ID: 25337579

SO-VID: bea94456-8e91-4226-b8ef-a8bf88dc18f5

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 09 June 2014

Date revision received : 24 June 2014

Date accepted : 24 June 2014

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Targeting Nrf2 Signaling to Combat Chemoresistance

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Most cited references 42

Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution.

Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2.

Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism.

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