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NF-E2-related factor 2 (Nrf2) protein is a basic-region leucine zipper transcription factor that defends against endogenous or exogenous stressors. By inducing several cytoprotective and detoxifying gene expressions, Nrf2 can increase the sensitivity of the cells to oxidants and electrophiles. Transient Nrf2 activation, by its specific activators, has protective roles against carcinogenesis and cancer development. However, permanent activation of Nrf2 promotes various cancer properties, comprising malignant progression, chemo/radio resistance, and poor patient prognosis. Taken together, these findings suggest that reaching an optimal balance between paradoxical functions of Nrf2 in malignancy may render a selective improvement to identify therapeutic strategies in cancer treatment. In this review, we describe lately discovered Nrf2 inducers and inhibitors, and their chemopreventive and/or anticancer activities.
The Nrf2 pathway signifies one of the most significant cell defense procedures against exogenous or endogenous stressors. Certainly, by increasing the expression of several cytoprotective genes, the transcription factor Nrf2 can shelter cells and tissues from multiple sources of damage including electrophilic, xenobiotic, metabolic, and oxidative stress. Notably, the aberrant activation or accumulation of Nrf2, a common event in many tumors, confers a selective advantage to cancer cells and is connected to malignant progression, therapy resistance, and poor prognosis. Therefore, lately, Nrf2 has arisen as a hopeful target in treatment of cancer, and many struggles have been made to detect therapeutic strategies intended at disrupting its pro-oncogenic role. By summarizing the outcomes from past and recent studies, this review provided an overview concerning the Nrf2 pathway and the molecular mechanisms causing Nrf2 hyperactivation in cancer cells. Finally, this paper also described some of the most promising therapeutic approaches that have been successfully employed to counteract Nrf2 activity in tumors, with a particular emphasis on the development of natural compounds and the adoption of drug repurposing strategies.
Despite the numerous efforts that researchers have carried out to improve the cancer outcomes, the overall cancer mortality rate has not significantly diminished over the past 30 years [1,2,3]. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced in the cells as the result of normal physiological procedures such as during inflammatory responses and mitochondrial aerobic respiration [4]. The elevated amounts of ROS and RNS in cancer cells can be responsible for triggering oxidative stress, which leads to DNA damage, alterations in tumor-suppressor genes and eventually initiation, development, and progression of cancer [4,5,6]. One of the key systems that confronts oxidative stress and xenobiotics is the Nrf2 signaling system.
Initially, somatic mutations of Keap1 were recognized in lung tumor tissues and cell lines [34], which are the second most common and significant genetic modifications in lung cancer [35]. However, Keap1 mutations have also been reported in other human cancers, for example, ovary (19%), gastric (11%), liver (9%), colon (8%), prostate (8%), and breast cancer (2%) [36,37,38]. These mutations were reported in several Keap1 domains, which result in inactivation of Keap1 and accumulation of Nrf2 in the nucleus of cancer cells [39,40,41,42]. Besides the Keap1 mutations, gain of function mutations of Nrf2 have also been identified in human cancers for example esophageal carcinoma, lung, head and neck cancer [23, 27]. Interestingly, almost all Nrf2 mutations occur specifically within either the ETGE (57%) or DLG (43%) motifs [24]. When the mutations occur at the ETGE motif, the high-affinity interaction between the keap1 and Nrf2 is destroyed [26], while DLG motif mutations lead to destruction of low-affinity interaction [27] (Fig. 2). Recently, Ooiet al. [43] identified somatic mutations of Cul3 in sporadic papillary renal cell carcinoma type-2 (PRCC2). They showed that Cul3 mutation can be the trigger of Nrf2 activation in some of the sporadic PRCC2.
Another protein involved in the disruption of Keap1-Nrf2 interactions is p62, which links to the autophagy-mediated degradation and contains a Keap1-interacting region (KIR) domain. Interestingly, the STGE (Ser-Thr-Gly-Glu) motif in KIR domain is similar to the Nrf2 ETGE motif and therefore is responsible for the direct interaction between Keap1 and p62 proteins [59,60,61]. It has been suggested that STGE-binding motif in p62 is bound to the Kelch domain of Keap1 with lower affinity than ETGE motif [62]. However, serine phosphorylation (S351) of the p62 STGE motif can remarkably increase this affinity and facilitate p62-dependent autophagic degradation of Keap1 which leading to subsequent activation of Nrf2 [63]. Significantly, the unusual accumulation of p62 has been identified in certain cancers such as hepatocellular carcinoma [64], lung [65, 66], gastric [67, 68], breast [69, 70], and colon cancers [67, 71], which might increase the malignant behavior of these tumors through improving Nrf2 activity.
Although the Nrf2 protein level primarily is regulated by the mutation/degradation process, a different study has been conducted on the control of the Nrf2 gene transcription. DeNicola et al. [72] showed that the transcriptional start site of Nrf2 has Jun and Myc binding sites and therefore, the expression of Nrf2 and its downstream genes can be increased remarkably by activating the oncogenic alleles of C-MYC, BRAF, and KRAS (C-MYCERT12, BRAFV619E, and KRASG12D) which followed by more reduction in the intracellular redox environment. In another study, promoter analysis of Nrf2 showed that in regulatory region in exon 1 of Nrf2, a 2-O-tetradecanoylphorbol-13-acetate (TPA) response element (TRE) was activated by KRAS in human non-small cell lung cancer (NSCLC) cells [73]. The oncogenic KRAS can induce antioxidant program through MAPK-mediated Nrf2 activation in pancreatic cancer. Furthermore, KRAS silencing or obstruction of MAP kinase signaling pathway efficiently decrease Nrf2 level and elevate ROS formation [74].
SFN is an effective dietary isothiocyanate, which found in cruciferous plants like Brussels sprouts and broccoli. SFN has anti-genotoxicity, anti-cancer and antioxidant activity as well as chemotherapeutic effect [79,80,81]. Besides enhancing cellular capacity in defense against oxidants, and electrophiles, it has been shown that sulforaphane is able to provoke apoptosis and reduce angiogenesis and cell cycle progression [82,83,84]. Interesting preclinical investigations show that sulforaphane prevents mice from forming carcinogen-mediated mammary carcinogenesis, lung, and gastric cancer, as well as colonic crypt foci [7, 85]. Previously, SFN was recognized as the most powerful activator of NQO1, but later it has been proved that the upregulation of NQO1 by SFN, indeed is regulated by the Nrf2-Keap1 signaling [86]. According to the in vivo experiments, site-directed mutagenesis and mass spectrometry analysis, it was evidenced that SFN can directly modify critical Keap1 cysteine 151 which followed by activation of the Nrf2-Keap1-ARE signaling [87, 88]. Thiols from Keap1 Kelch domain and isothiocyanate from SFN are covalently bound together which lead to the releasing of Nrf2 from Keap1 and finally inducing phase II metabolic enzymes [89, 90]. In another study, Kobayashi et al. categorized SFN as class 1 ARE inducers. Moreover, they found that the induction of ARE-regulated genes in zebrafish via sulforaphane is highly dependent on keap1 Cys151 [88]. It has been shown that SFN has a protective role against cancer development in different kinds of transgenic and carcinogen-induced tumor models (reviewed [91, 92]). In an animal study, Kalpana et al. revealed the inhibitory effect of SFN on benzo(a)pyrene (B(a)P)-induced lung cancer in the mouse, with emphasis on the effect of SFN on Nrf2 signal pathway [93]. Besides, in some clinical trial studies, the effect of SFN, as an Nrf2 activator, was evaluated in patients with colon, prostate, breast, and pancreatic cancers [79,80,81,82]. SFN can concomitantly upregulate Nrf2 and its downstream target genes, including HO1, NQOs, GSTs, and UGTs, rapidly in less than 30 min [94]. Another study demonstrated that sulforaphane epigenetically restored Nrf2 mRNA expression through the demethylation of its promoter CpGs in TRAMP-C1 and JB6 cells [95, 96].
OPZ also may enhance the binding activity of Nrf2 to the ARE [100, 106]. Jia et al. [107] showed that dithiolethiones potentially have the ability to Keap1 cysteine modification. For example, 3H-1,2-dithiole-3-thione, which is structurally similar to OPZ, induces intermolecular disulfide cross-linking between two Keap1 monomers by targeting Cys273 and Cys288 [108]. Moreover, another study proved that Nrf2 is responsible for the chemopreventive effects of OPZ against bladder cancer [109].
EGCG is known to be a potent inducer of Nrf2 among several polyphenols found in green tea extract [110]. EGCG has anti-oxidative stress and anti-inflammatory activities through the downregulation of cyclooxygenase-2 and nitric oxide synthase [111]. According to the previous studies, EGCG has protective activity against experimentally induced prostate [112], fore-stomach [113], lung [114], skin [115], breast [116], and colon cancer [117]. Khan et al. [118] reported that EGCG could inhibit the cell adhesion function and downregulate the expression of matrix metalloproteinases that results in a reduction in angiogenesis, metastasis, and invasion of cancer cells. In addition to its ability to function as an anti-angiogenic agent, EGCG can induce apoptosis in numerous types of cancers by stabilizing the tumor suppressor p53 [119] and inactivating some transcription factors [119, 120].
DMF-related activation of Nrf2 exerts cytoprotective actions in different cell types, for example, splenocytes, embryonic primary cortical cells, astrocytes, microglial cells, renal fibroblasts, and mesangial cells. Moreover, a growing body of evidence suggests that DMF suppresses proliferation, invasion, and angiogenesis and promotes apoptosis of various cancer cells [135,136,137]. An animal study showed that DMF has pro-apoptotic and anti-proliferative activities in melanoma cells and postpones progression and metastasis of melanoma [138]. 59ce067264