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Gado, F.; Ferrario, G.; Vedova, L.D.; Zoanni, B.; Altomare, A.; Carini, M.; Aldini, G.; D’amato, A.; Baron, G. Targeting Nrf2 and NF-κB Signaling Pathways in Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/41198 (accessed on 20 May 2024).
Gado F, Ferrario G, Vedova LD, Zoanni B, Altomare A, Carini M, et al. Targeting Nrf2 and NF-κB Signaling Pathways in Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/41198. Accessed May 20, 2024.
Gado, Francesca, Giulio Ferrario, Larissa Della Vedova, Beatrice Zoanni, Alessandra Altomare, Marina Carini, Giancarlo Aldini, Alfonsina D’amato, Giovanna Baron. "Targeting Nrf2 and NF-κB Signaling Pathways in Cancer" Encyclopedia, https://encyclopedia.pub/entry/41198 (accessed May 20, 2024).
Gado, F., Ferrario, G., Vedova, L.D., Zoanni, B., Altomare, A., Carini, M., Aldini, G., D’amato, A., & Baron, G. (2023, February 14). Targeting Nrf2 and NF-κB Signaling Pathways in Cancer. In Encyclopedia. https://encyclopedia.pub/entry/41198
Gado, Francesca, et al. "Targeting Nrf2 and NF-κB Signaling Pathways in Cancer." Encyclopedia. Web. 14 February, 2023.
Targeting Nrf2 and NF-κB Signaling Pathways in Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/molecules28031356

Plant secondary metabolites, known as phytochemicals, have gained much attention in light of the “circular economy”, to reutilize waste products deriving from agriculture and food industry. Phytochemicals are known for their onco-preventive and chemoprotective effects, among several other beneficial properties. Apple phytochemicals have been extensively studied for their effectiveness in a wide range of diseases, cancer included.

phytochemicals apple polyphenols Nrf2 signaling pathway NF-κB signaling pathway

1. The Role of Nrf2 in the Cancer Environment

The complex relationship between this gene and cancer comes from its main function to detoxify the cell environment: its regulation and modulation has been deemed a “double-edge sword” [1] with multiple intricacies [2]. The overexpression of Nrf2 due to Nrf2 machinery mutations (e.g., somatic mutations in Keap1, Nrf2, or Cul3; epigenetic DNA methylation of Keap1; etc.) or Nrf2/Keap1 post-translational modifications, promote cancer development and resistance [3][4][5][6]. Indeed, Nrf2 constitutive activation can lead to metabolic reprogramming for cell proliferation, and to an increase antioxidant and detoxification activity, helping cancer cells withstand the damaging effects of chemotherapy and radiation [1][2]. In such type of cancers, Nrf2 inhibitors are desired, but, to date, no FDA approved drugs are available. Moreover, Nrf2 inducers should be avoided. On the other hand, Nrf2 could be found suppressed in some types of cancers, as evidenced in prostate tumors of the transgenic adenocarcinoma of mouse prostate (TRAMP) mice [7] and in a model of the stepwise human mesenchymal stem cell (MSC) leading to tumor growth and poorer survival rates [8]. In particular, regarding TRAMP mice, the suppression of Nrf2 was found to be due to a hypermethylation of Nrf2 promoter [9]. Besides altered expression of Nrf2, this transcription factor plays a pivotal role in chronic inflammation, which triggers cancer onset. In this context, Nrf2 can control the expression of cytoprotecting proteins, such as HO-1 and SOD, and suppress proinflammatory gene activation. In the last two conditions, Nrf2 inducers could have a chemo-preventive role. Among the known inducers are oxidable diphenols, which are highly concentrated in vegetable matrices. In particular, the active isomers are ortho- and paradiphenols because of their transformation into the respective quinones under oxidative stress conditions. These last can easily bind to Keap1 thiol groups, thus activating Nrf2 [9]. Nevertheless, Potter et al. observed that the CYP1B1 enzyme, selectively overexpressed in many human tumors having aromatic hydroxylation activity, catalyze the addition of a hydroxyl group to aromatic compounds, and so transform inactive phenolic compounds in oxidable diphenols [10]. In this context, polyphenolic compounds can act as Nrf2 inducers directly, in the case of 1,2-/1,4-diphenols, or after their activation through the CYP1B1 enzyme.

Apple Phytochemicals as Nrf2 Inducers

Apples are a rich source of phytochemicals, in particular of polyphenols, which can act as Nrf2 inducers due to their chemical structure. The oxidative diphenols in apple and apple-derived products are mainly represented by 1,2-diphenols; quercetin and its glycosides are the most abundant flavonols, along with procyanidins and their monomers catechin and epicatechin, and chlorogenic acid [11].
In vivo studies demonstrated Nrf2 activation by polyphenols from different apple sources [12][13][14][15]. In physiological conditions, Sprague-Dawley rats orally treated with different types of apple products (juices and smoothies) showed a product-dependent increase in Nrf2 at the colonic level but not in the liver; the highest response was observed after the intake of the apple product with the highest content of procyanidins [12]. Sharma et al. observed a dose-dependent Nrf2 induction accompanied by a reduction in liver necrosis in a mouse model of oxidative hepatotoxicity after treatment with apple pomace [13]. Furthermore, Xu et al. found that Nrf2 increased in pig liver after treatment with apple polyphenols [14]. A recent study on pig model supplemented with 400 mg/kg and 800 mg/kg of apple polyphenols confirmed an Nrf2 dose-dependent induction in pigs’ jejunum and intestinal mucosa, and, through a further investigation on IPEC-J2 cells, Huang et al. demonstrated that the Nrf2/Keap1 pathway modulates the effect of apple polyphenols on intestinal antioxidant capacity and tight-junction protein expressions (ZO-1, occludin and claudin-1), thus ameliorating barrier function [15].
Nondiphenol apple components—phlorizin and ursolic acid—showed an activity towards Nrf2. Phlorizin is the glucoside derivative of the dihydrochalcone phloretin. In vitro and in vivo studies supported its involvement in Nrf2 activation [16][17][18], but no one demonstrated the interaction mechanism between the transcription factor and the polyphenol. Molecular docking simulations suggested [18][19] non-covalent interactions: hydrogen bond, polar and van der Waals interactions. Ursolic acid also activates Nrf2, but through a different mechanism: Kim et al. demonstrated that it decreases Nrf2 promoter methylation by the negative regulation of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) [20].

2. NF-κB Inhibition by Apple Polyphenols Ameliorate Inflammation in Cancer

Increasing evidence indicates that chronic inflammation leads to the onset of chronic diseases including cardiovascular and neurological disorders, diabetes and cancer. The possibility to control and reduce an inflammation condition through phytochemicals, such as those from apples, may be an effective strategy to reduce the risk of incurring these kinds of diseases.
A recent study carried out to assess the possible protective effects of apple polyphenols in an animal model of hyperlipidaemia suggested that the anti-inflammatory action of apple polyphenols may have beneficial effects on atherosclerosis by improving endothelial dysfunction and plaque formation through the suppression of the ROS/MAPK/NF-kB signalling pathway and the subsequent reduction in the expression of proinflammatory molecules (CCL-2, ICAM, and VCAM-1) [21].
Several mechanisms have been investigated to explain the reported anti-inflammatory effects of apple polyphenols. Jung et al. studied the anti-inflammatory properties of apple juice extract and its single major constituents in four human immunorelevant cell lines (DLD-1, T84, MonoMac6, Jurkat). The results showed the treatment significantly inhibited the expression of proinflammatory genes regulated by the transcription factor NF-κB (TNF-α, IL-1β, CXCL9, CXCL10), as well as inflammatory enzymes (COX-2, CYP3A4) and transcription factors (STAT1, IRF1), at concentrations of 100–200 µg/mL in stimulated MonoMac6 cells. Moreover, further screening of major compounds included in the extract revealed that procyanidin B1, procyanidin B2, and phloretin are mainly responsible for the effects of the tested extract [22]. Similarly, it was found that cultivars with high levels of procyanidins were the most effective at inhibiting NF-κB activation [23]. However, it should be considered that procyanidins are not absorbed in vivo, but catabolised by the gut microflora at the intestinal level, as recently described by several in vivo studies [24][25].
NF-κB plays a critical role in the regulation of gene expression involved in cancer, and its dysregulation has been linked extensively to the development and progression of various types of cancer, including breast, ovarian, prostate and colorectal cancer. In this regard, inhibiting NF-κB signalling could be a promising target for cancer treatment [26]. Nevertheless, the mechanisms of how apple polyphenols work have not been fully understood.
Yoon et al. evaluated the effects of apple extracts on NF-κB activation in human breast cancer MCF-7 cells, and suggested that apple extracts may inhibit the activation of NF-κB by inhibiting the proteasomal activity of those cells [27]. In addition, the synthesis of new triterpene derivatives of oleanolic and ursolic acid demonstrated the involvement of NF-kB in the modulation of their anticancer effects on tumour cell lines [28]. Quercetin has also been demonstrated to inhibit TNF-α NF-κB signalling pathway activation in human umbilical vein endothelial cells (HUVECs) [29].
A recent study on an endometrial cancer mouse model demonstrated that an apple seed extract promotes the apoptosis of cancer cells by downregulating NF-κB [30].
A polyphenol extract from Annurca apples revealed an interesting antitumour mechanism in triple-negative MDA-MB-231 human breast carcinoma cells: the extract promoted ROS generation leading to c-Jun-N-terminal kinase (JNK) activation, thus promoting apoptosis and downregulated NF-κB, which is interconnected to JNK by reducing its apoptotic activity [31].
The real mechanism through which phytochemicals inhibit the NF-κB activation is not well established, and probably more than one can occur. Nevertheless, some studies brought attention to IκB kinase (IKK), in which inactivation was observed in different cell types by quercetin treatment [32]. IKK phosphorylation is fundamental for NF-κB activation, so IKK can be a possible target. It has been observed that 4-Hydroxynonenal (HNE), a common electrophile molecule deriving from lipid oxidation, is able to bind a cysteine residue of IKK inhibiting IkBα degradation [33]. Considering that quercetin is an oxidable 1,2-diphenol, it can probably react with the cysteine of IKK and exert its anti-inflammatory activity. This hypothesis could be extended to other oxidable diphenols present in apple and apple-derived products, but always considering their bioavailability. Of course, this proposed mechanism should be investigated experimentally.

3. Nrf2 and NF-κB Pathways Crosstalk

In this context, the discussion about Nrf2 and its role may not be separated from the discussion about NF-κB signaling. As already mentioned, a dysregulation of both Nrf2 and NF-κB signaling has been linked to various diseases, including cancer. Nrf2 is activated by high level of oxidative stress and plays a role in the transactivation of genes encoding for antioxidant enzymes. An intermediate amount of reactive oxygen species (ROS) activates NF-κB and triggers an inflammatory response, while a high level of ROS leads to perturbation of the mitochondrial permeability transition pore and disruption of electron transfer, resulting in apoptosis or necrosis. There is evidence to suggest that Nrf2 and NF-κB signaling may crosstalk with each other, with Nrf2 activation potentially modulating the expression and transactivation of NF-κB [34].
The regulation of Nrf2 and NF-κB is complex and involves multiple mechanisms. One of these regards the competition between Nrf2 and p65 for the CBP-p300 transcriptional co-activator complex, which transfers an acetyl moiety to the lysine residues of the transcription factors enhancing gene transcription. In the presence of both, CBP seems to have a preference for binding and favoring κB transcription genes [35].
Several other proteins are also involved in the regulation of Nrf2 and NF-κB. RAC1, a small GTPase, activates Nrf2-mediated HO-1 expression, which in turn dampens the proinflammatory activity of NF-κB. Keap1 itself negatively regulates NF-κB through the stabilization of IKBα [36]. Besides Keap1, the β-TrCP protein also regulates nuclear Nrf2 levels by recognizing, binding and degrading the transcription factor after its phosphorylation mediated by GSK3β [37]. p65 is also a substrate of GSK3β and β-TrCP; the first modulates with both positive and negative effects, depending on the cellular context, and the second augments NF-κB through IκBα degradation [38][39][40]. Other proteins involved in the regulation of Nrf2 and NF-κB include p62, which enhances Nrf2 activity through the autophagosomal degradation of Keap1 [41], and promotes the nerve growth factor-induced activation of the NF-κB pathway by ubiquitinylating tumor necrosis factor receptor-associated factor 6 (TRAF6) [42], and MafK, which facilitates the interaction of p65 and CBP. Nrf2 can also act as a dimer with sMaf proteins to modulate the transcriptional activity of p65 [43].
Most of the phytochemicals with chemopreventive potential, due to their demonstrated synergism in modulating the Nrf2 and NF-κB pathways, are derived from fruits and vegetables.
For this reason, several studies evaluated the influence of natural matrix on the Nrf2 and NF-κB pathways. Therefore, the application of phytochemical combinations as modulators of NF-κB and Nrf2, and, in the end, cancer prevention or therapy, seems to be an appealing approach.
Only two recent studies reported the simultaneous activity of apple products on both Nrf2 and NF-κB. The first is an in vitro study on polyphenols from thinned young apples which evaluate the activation of Nrf2 and the inhibition of NF-κB through two different approaches: the authors observed a dose-dependent activation of Nrf2 and a dose-dependent reduction of NF-κB using cell models with gene reporters; the second approach is based on quantitative proteomics, which gives a complete overview of the proteins up- or downregulated. After the inflammatory stimulus, an increase of NF-κB is observed, while the treatment with apple extract made NF-κB return to homeostatic conditions. Moreover, both in physiological and inflammatory conditions, the extract activates the Nrf2 pathway (with an increase, e.g., of HO-1) and upregulates enzymes of the pentose-phosphate pathway, leading to the production of NADPH, a cofactor of the enzymes NADPH–cytochrome P450 reductase (POR) and biliverdin reductase (BLVRB), which produce bilirubin, a potent antioxidant against lipid peroxidation [44]. The second is an in vivo study on the effects of apple polyphenols in weaning piglets, evaluating the antioxidant capacity, immune and inflammatory response, together with intestinal barrier function. Two different dosages of apple polyphenols were evaluated, 400 and 800 mg/kg, versus control. Nrf2 was found significantly upregulated, together with HO-1 at the dose 400 mg/kg, while NF-κB was significantly downregulated at the dose of 800 mg/kg. Moreover, the supplementation with apple polyphenols ameliorates the intestinal villi shape, improving jejunal absorption capacity [45].
Besides the activity of apple products, some evidence of apple phytochemical activity on both Nrf2 and NF-κB is reported: isolated studies on NF-κB inhibition and Nrf2 activation by ursolic acid demonstrated its activity on both transcription factors, as mentioned in the previous paragraphs.

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Subjects: Biochemistry & Molecular Biology; Chemistry, Medicinal
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Francesca Gado
,
Giulio Ferrario
,
Larissa Della Vedova
,
Beatrice Zoanni
,
Alessandra Altomare
,
Marina Carini
,
Giancarlo Aldini
,
Alfonsina D’Amato
,
Giovanna Baron
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Revisions: 2 times (View History)
Update Date: 15 Feb 2023
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