Nrf2 is a potential therapeutic target in radioresistance in human cancer

doi:10.1016/j.critrevonc.2013.09.001

Critical Reviews in Oncology/Hematology

Volume 88, Issue 3, December 2013, Pages 706-715

https://doi.org/10.1016/j.critrevonc.2013.09.001 Get rights and content

Abstract

Radiation therapy can effectively kill cancer cells through ROS generation. Cancer cells with upregulated antioxidant systems can develop high radioresistance ability, and the transcription factor NF-E2-related factor 2 (Nrf2) is a key regulator of the antioxidant system. Currently, there are numerous data indicating the important role of Nrf2 in cancer radioresistance. In this review, we summarize the aberrant regulation of Nrf2 in radioresistant cells and discuss the effects and underlying mechanism of Nrf2 in promoting radioresistance. These findings suggest that Nrf2 might be a potential therapeutic target in cancer radiation resistance or a promising radioprotector for normal organs during radiation therapy in the future.

Introduction

Reactive oxygen species (ROS) are implicated in diverse cellular processes, including metabolism and signaling, and they play important roles in a variety of diseases, including cancer. ROS can be produced by physical or chemical stimuli [1], [2]. ROS are toxic at high levels in mammalian cells and cause DNA damage and membrane oxidative damage [3]. Ionizing radiation has been shown to significantly contribute to the generation of ROS in a variety of cells, and it can induce DNA damage and repair, apoptosis, cell cycle control, signal transduction, and oxidative stress responses inside the cell [4], [5]. Radiation therapy is now commonly accepted as one of the most effective treatment for a variety of malignant cancers of different origins and stages [6]. Radiation therapy can effectively kill cancer cells through ROS generation. However, some cancer cells with upregulated redox and antioxidant ability can escape from the damaging effects of radiation by scavenging ROS, leading to radioresistance [7], [8]. Therefore, it is urgent to solve the radioresistance of these cancer cells to improve the curative effect of cancer therapy. Studies have shown that upregulating antioxidant enzyme expression protects cancer cells from radiation therapy, whereas blocking these defense systems confers increased sensitivity [7], [9], [10]. The expression of these antioxidant enzymes is mostly regulated by the transcription factor NF-E2-related factor 2 (Nrf2). Nrf2, a member of the cap’n’collar family of basic leucine zipper transcription factors, is an essential activator of the coordinated transcription of genes encoding antioxidant enzymes and phase II detoxifying enzymes through the antioxidant response element (ARE) [11]. In this review, we will focus on the role of Nrf2 in regulating the radioresistance of human cancer and its potential as a target for radiation therapy in cancer.

Section snippets

The main mechanism of radioresistance in human cancer

Radiation therapy is one of the most widely accepted and effective cancer treatments, and it induces apoptosis in cancer cells through the induction of direct and indirect DNA damage [12]. Direct DNA damage is caused by ionizing photons and ionizing particles, whereas free radicals derived from ionized water molecules contribute to indirect DNA damage [13], [14]. Radiation therapy appears capable of successfully controlling many types of cancer, but its effectiveness is severely compromised by

The role of Nrf2 in radioresistance

Nrf2 is a key transcriptional regulator of genes encoding numerous cytoprotective enzymes, and it is induced by environmental and endogenously derived oxidative/electrophilic agents [29], [30]. Under basal conditions, Nrf2 is sequestered by the repressor Kelch-like ECH-associated protein1 (Keap1) in the cytoplasm and rapidly degraded in a ubiquitin-proteasome-dependent manner, whereas Nrf2 escapes Keap1-mediated repression under conditions of oxidative stress [31], [32]. Nrf2 protects

Targeting Nrf2 to overcome radioresistance

The gain of Nrf2 function by a dysfunctional Keap1–Nrf2 interaction or other inducers has been implicated in the resistance of cancer cells to radiation therapy. Thus far, strategies to inhibit the levels and/or activity of Nrf2 have been developed and used in studies on Nrf2 to improve the efficiency of radiation therapy. As shown in Table 1, increasing evidence demonstrates that Nrf2 down-regulation facilitates the re-sensitization of cells to ionizing radiation. The currently available Nrf2

Conclusions and perspectives

In conclusion, Nrf2 is believed to play an important role in cancer radioresistance, and the possible mechanisms of Nrf2 in radioresistance are shown in Fig. 1. Aberrantly increased Nrf2 activity or expression occurs in cancer cells, conferring radioresistance. The up-regulation of Nrf2 target genes, such as HO-1, NQO1 and Prx1, has also been confirmed in relation to cancer radioresistance. The mechanisms of Nrf2 in radioresistance include not only Nrf2 target gene activation but also

Reviewers

Chunxia Cao Ph.D., Research Associate, University of Florida, Department of Medicine, 2033 Mowry Rd., CGRC, room 365, Gainesville, FL 32610, United States.

Masayuki Yamamoto Ph.D., Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.

Toshihisa Ishikawa, Ph.D., RIKEN Center for Life Science Technology, 1-7-22 Suehiro-cho, Tsurumi-ku, 230-0045 Yokohama, Japan.

Acknowledgements

This work was supported by Chinese National Natural Science Foundation Projects (NSFC 81301922 and 81302055).

Dr. Suna Zhou M.D., Ph.D. of Oncology, is an attending doctor in the Radiology Department, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China. Her research interest is in exploring the exact molecular mechanism in radioresistance.

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Dr. Mingxin Zhang received his B.S. degree, M.S. degree and Ph.D. degree at Xi’an Jiaotong University. Then he becomes an attending doctor in Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University. His current research interests include the role of microRNAs (miRNAs) in cancer, effect of Nrf2 in cancer, and tumor biomarkers in diagnosis and prognosis.

Prof. Jun Liang received his B.S. degree and M.S. degree at Fourth Military Medical University. He is currently the Director of Radiology Department in Tangdu Hospital. His current research interests are to define the different types of radiation therapy and discuss scientific advances that improve the effectiveness of this treatment.

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Nrf2 is a potential therapeutic target in radioresistance in human cancer

Abstract

Introduction

Section snippets

The main mechanism of radioresistance in human cancer

The role of Nrf2 in radioresistance

Targeting Nrf2 to overcome radioresistance

Conclusions and perspectives

Reviewers

Acknowledgements

Drug Resist Updat

Cancer Lett

Free Radic Biol Med

J Biol Chem

Int J Radiat Oncol Biol Phys

Semin Radiat Oncol

Radiother Oncol

Free Radic Biol Med

Cancer Lett

Biochem Biophys Res Commun

Adv Enzyme Regul

Mol Cell

Biochem Biophys Res Commun

J Pathol

Int J Biochem Cell Biol

J Biol Chem

J Biol Chem

Lung Cancer

Lung Cancer

J Invest Dermatol

Curr Top Cell Regul

Free Radic Biol Med

Int J Radiat Oncol Biol Phys

Biochem Pharmacol

Arch Biochem Biophys

Cell Stress Chaperones

Free Radic Biol Med

Cancer Lett

Cell Metab

J Biol Chem

Cancer Cell

Biochim Biophys Acta

ROS, stress-activated kinases and stress signaling in cancer

EMBO Rep

Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy

J Natl Cancer Inst

Antioxidants reduce consequences of radiation exposure

Adv Exp Med Biol

The role of p53 in determining sensitivity to radiotherapy

Nat Rev Cancer

Increased expression of antioxidant enzymes in radioresistant variant from U251 human glioblastoma cell line

Int J Mol Med

Association of reactive oxygen species levels and radioresistance in cancer stem cells

Nature

Loss of Keap1 function in prostate cancer cells causes chemo-and radio-resistance and promotes tumor growth

Mol Cancer Ther

Free radicals in biology: oxidative stress and the effects of ionizing radiation

Int J Radiat Biol

Initial events in the cellular effects of ionizing radiations: clustered damage in DNA

Int J Radiat Biol

Radiation resistance of cancer stem cells: the 4 R's of radiobiology revisited

Stem Cells

Antioxidants and radiation therapy

J Nutr

Antisense of human peroxiredoxin II enhances radiation-induced cell death

Clin Cancer Res

The role of peroxiredoxin II in radiation-resistant MCF-7 breast cancer cells

Cancer Res

Do antioxidants interfere with radiation therapy for cancer

Integr Cancer Ther

Identification of human brain tumour initiating cells

Nature

Prospective identification of tumorigenic prostate cancer stem cells

Cancer Res

Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma

Proc Natl Acad Sci U S A

Phenotypic characterization of human colorectal cancer stem cells

Proc Natl Acad Sci U S A