bims-nurfca 2023-02-12 papers

bims-nurfca

Biomed News

on NRF2 and Cancer

Issue of 2023‒02‒12
twelve papers selected by
Caner Geyik
Istinye University

Kynureninase Upregulation Is a Prominent Feature of NFR2-Activated Cancers and Is Associated with Tumor Immunosuppression and Poor Prognosis.
The dual role of Nrf2 in melanoma: a systematic review.
Exploring structural effects in a new class of NRF2 inhibitors.
NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress.
NRF2 signaling pathway: A comprehensive prognostic and gene expression profile analysis in breast cancer.
Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer.
DNMT3A R882H mutation promotes acute leukemic cell survival by regulating glycolysis through the NRF2/NQO1 axis.
SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation.
UBE2E2 enhances Snail-mediated epithelial-mesenchymal transition and Nrf2-mediated antioxidant activity in ovarian cancer.
Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-Dependent Antioxidant Defense System.
Flavonoids of Haloxylon salicornicum (Rimth) prevent cisplatin-induced acute kidney injury by modulating oxidative stress, inflammation, Nrf2, and SIRT1.
Targeting Nrf2 and NF-κB Signaling Pathways in Cancer Prevention: The Role of Apple Phytochemicals.

Cancers (Basel). 2023 Jan 29. pii: 834. [Epub ahead of print]15(3):

Kynureninase Upregulation Is a Prominent Feature of NFR2-Activated Cancers and Is Associated with Tumor Immunosuppression and Poor Prognosis.

Ricardo A León-Letelier, Ali H Abdel Sater, Yihui Chen, Soyoung Park, Ranran Wu, Ehsan Irajizad, Jennifer B Dennison, Hiroyuki Katayama, Jody V Vykoukal, Samir Hanash, Edwin J Ostrin, Johannes F Fahrmann.

  The nuclear factor erythroid 2-related factor 2 (NRF2) pathway is frequently activated in various cancer types. Aberrant activation of NRF2 in cancer is attributed to gain-of-function mutations in the NRF2-encoding gene NFE2L2 or a loss of function of its suppressor, Kelch-like ECH-associated protein 1 (KEAP1). NRF2 activation exerts pro-tumoral effects in part by altering cancer cell metabolism. Previously, we reported a novel mechanism of NRF2 tumoral immune suppression through the selective upregulation of the tryptophan-metabolizing enzyme kynureninase (KYNU) in lung adenocarcinoma. In the current study, we explored the relevance of NRF2-mediated KYNU upregulation across multiple cancer types. Specifically, using a gene expression dataset for 9801 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), we demonstrated that elevated KYNU parallels increased gene-based signatures of NRF2-activation and that elevated tumoral KYNU mRNA expression is strongly associated with an immunosuppressive tumor microenvironment, marked by high expression of gene-based signatures of Tregs as well as the immune checkpoint blockade-related genes CD274 (PDL-1), PDCD1 (PD-1), and CTLA4, regardless of the cancer type. Cox proportional hazard models further revealed that increased tumoral KYNU gene expression was prognostic for poor overall survival in several cancer types, including thymoma, acute myeloid leukemia, low-grade glioma, kidney renal papillary cell carcinoma, stomach adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC). Using PDAC as a model system, we confirmed that siRNA-mediated knockdown of NRF2 reduced KYNU mRNA expression, whereas activation of NFE2L2 (the coding gene for NRF2) through either small-molecule agonists or siRNA-mediated knockdown of KEAP1 upregulated KYNU in PDAC cells. Metabolomic analyses of the conditioned medium from PDAC cell lines revealed elevated levels of KYNU-derived anthranilate, confirming that KYNU was enzymatically functional. Collectively, our study highlights the activation of the NRF2-KYNU axis as a multi-cancer phenomenon and supports the relevance of tumoral KYNU as a marker of tumor immunosuppression and as a prognostic marker for poor overall survival.

Keywords:  KYNU; NRF2; immunosuppression; multi-cancer; prognosis

DOI:  https://doi.org/10.3390/cancers15030834
BMC Mol Cell Biol. 2023 Feb 06. 24(1): 5

The dual role of Nrf2 in melanoma: a systematic review.

Zahra Malakoutikhah, Zahra Mohajeri, Nasim Dana, Shaghayegh Haghjooy Javanmard.

  Melanoma is the most lethal type of skin cancer that originates from the malignant transformation of melanocytes. Although novel treatments have improved patient survival in melanoma, the overall prognosis remains poor. To improve current therapies and patients outcome, it is necessary to identify the influential elements in the development and progression of melanoma.Due to UV exposure and melanin synthesis, the melanocytic lineage seems to have a higher rate of ROS (reactive oxygen species) formation. Melanoma has been linked to an increased oxidative state, and all facets of melanoma pathophysiology rely on redox biology. Several redox-modulating pathways have arisen to resist oxidative stress. One of which, the Nrf2 (nuclear factor erythroid 2-related factor 2), has been recognized as a master regulator of cellular response to oxidative or electrophilic challenges. The activation of Nrf2 signaling causes a wide range of antioxidant and detoxification enzyme genes to be expressed. As a result, this transcription factor has lately received a lot of interest as a possible cancer treatment target.On the other hand, Nrf2 has been found to have a variety of activities in addition to its antioxidant abilities, constant Nrf2 activation in malignant cells may accelerate metastasis and chemoresistance. Hence, based on the cell type and context, Nrf2 has different roles in either preventing or promoting cancer. In this study, we aimed to systematically review all the studies discussing the function of Nrf2 in melanoma and the factors determining its alteration.

Keywords:  Chemoresistance; Melanoma; Metastasis; Nrf2; Oxidative stress; Systematic review

DOI:  https://doi.org/10.1186/s12860-023-00466-5
RSC Med Chem. 2023 Jan 25. 14(1): 74-84

Exploring structural effects in a new class of NRF2 inhibitors.

Zhilin Hou, Lizbeth Lockwood, Di Zhang, Christopher J Occhiuto, Linqing Mo, Kelly E Aldrich, Hayden E Stoub, Kathleen A Gallo, Karen T Liby, Aaron L Odom.

NRF2 is a transcription factor that controls the cellular response to various stressors, such as reactive oxygen and nitrogen species. As such, it plays a key role in the suppression of carcinogenesis, but constitutive NRF2 expression in cancer cells leads to resistance to chemotherapeutics and promotes metastasis. As a result, inhibition of the NRF2 pathway is a target for new drugs, especially for use in conjunction with established chemotherapeutic agents like carboplatin and 5-fluorouracil. A new class of NRF2 inhibitors has been discovered with substituted nicotinonitriles, such as MSU38225. In this work, the effects on NRF2 inhibition with structural changes were explored. Through these studies, we identified a few compounds with as good or better activity than the initial hit but with greatly improved solubility. The syntheses involved a variety of metal-catalyzed reactions, including titanium multicomponent coupling reactions and various Pd and Cu coupling reactions. In addition to inhibiting NRF2 activity, these new compounds inhibited the proliferation and migration of lung cancer cells in which the NRF2 pathway is constitutively activated.

DOI: https://doi.org/10.1039/d2md00211f
Cell Death Discov. 2023 Feb 04. 9(1): 43

NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress.

Yi Wang, Yuxin Zan, Yingying Huang, Xiaoyun Peng, Shinan Ma, Ji Ren, Xiao Li, Lin Wei, Xiaoli Wang, Yahong Yuan, Junming Tang, Zhongqun Zhan, Zhixiao Wang, Yan Ding.

Doxorubicin (DOX) is a commonly used antitumor drug, but its application has been limited because of its strong cardiac damage. This study aims to explore the role of NSUN2 in DOX-induced heart injury. C57BL/6J mice were intraperitoneally injected with 20 mg/Kg DOX to induce heart injury. After 3 days, the cardiac function, cardiac histopathology, myocardial apoptosis, and the expression level of NSUN2 were detected. In vitro, H9C2 cells were transfected with NSUN2 siRNA or overexpressed lentivirus and then treated with 500 ng/ml DOX. After 24 h, the changes in reactive oxygen species (ROS), apoptosis, and NSUN2 expression were detected. After DOX treatment, both in vitro and in vivo experiments showed that the cardiac function decreased, the number of apoptotic cells increased, and the expression level of NSUN2 increased. Interfering the expression of NSUN2 by siRNA promoted DOX-induced heart injury, while overexpression of NSUN2 could inhibit DOX-induced heart injury. Further study showed that NSUN2 promoted antioxidative stress by upregulating the Nrf2 protein level. In addition, NSUN2 overexpression could increase the half-life of Nrf2 mRNA. m5C RNA methylation immunoprecipitation (MeRIP) also showed that the level of Nrf2 m5C mRNA was significantly increased in NSUN2 overexpressed group when compared to the GFP group. NSUN2 enhances the expression of Nrf2 by promoting Nrf2 mRNA m5C modification and enhances its antioxidative stress effect to alleviate DOX-induced myocardial injury.

DOI: https://doi.org/10.1038/s41420-022-01294-w
Pathol Res Pract. 2023 Jan 24. pii: S0344-0338(23)00041-9. [Epub ahead of print]243 154341

NRF2 signaling pathway: A comprehensive prognostic and gene expression profile analysis in breast cancer.

Negin Soghli, Hassan Yousefi, Tohid Naderi, Aysan Fallah, Amin Moshksar, Farzaneh Darbeheshti, Cecilia Vittori, Mahsa Rostamian Delavar, Ali Zare, Habib Sadeghi Rad, Abtin Kazemi, Amirreza Bitaraf, Bashdar Mahmud Hussen, Mohammad Taheri, Elena Jamali.

  Breast cancer is the most frequently diagnosed malignant tumor in women and a major public health concern. NRF2 axis is a cellular protector signaling pathway protecting both normal and cancer cells from oxidative damage. NRF2 is a transcription factor that binds to the gene promoters containing antioxidant response element-like sequences. In this report, differential expression of NRF2 signaling pathway elements, as well as the correlation of NRF2 pathway mRNAs with various clinicopathologic characteristics, including molecular subtypes, tumor grade, tumor stage, and methylation status, has been investigated in breast cancer using METABRIC and TCGA datasets. In the current report, our findings revealed the deregulation of several NRF2 signaling elements in breast cancer patients. Moreover, there were negative correlations between the methylation of NRF2 genes and mRNA expression. The expression of NRF2 genes significantly varied between different breast cancer subtypes. In conclusion, substantial deregulation of NRF2 signaling components suggests an important role of these genes in breast cancer. Because of the clear associations between mRNA expression and methylation status, DNA methylation could be one of the mechanisms that regulate the NRF2 pathway in breast cancer. Differential expression of Hippo genes among various breast cancer molecular subtypes suggests that NRF2 signaling may function differently in different subtypes of breast cancer. Our data also highlights an interesting link between NRF2 components' transcription and tumor grade/stage in breast cancer.

Keywords:  Breast cancer; METABRIC; Methylation; NRF2; TCGA

DOI:  https://doi.org/10.1016/j.prp.2023.154341
Cancer Metab. 2023 Feb 08. 11(1): 3

Tamoxifen induces radioresistance through NRF2-mediated metabolic reprogramming in breast cancer.

F V Naumann, F C G J Sweep, G J Adema, W J M Peeters, J W M Martens, J Bussink, P N Span.

  BACKGROUND: Recently, we reported that tamoxifen-resistant (TAM-R) breast cancer cells are cross-resistant to irradiation. Here, we investigated the mechanisms associated with tamoxifen-induced radioresistance, aiming to prevent or reverse resistance and improve breast cancer treatment.METHODS: Wild-type ERα-positive MCF7 and ERα-negative MDA-MB-231 breast cancer cells and their TAM-R counterparts were analyzed for cellular metabolism using the Seahorse metabolic analyzer. Real-time ROS production, toxicity, and antioxidant capacity in response to H2O2, tamoxifen, and irradiation were determined. Tumor material from 28 breast cancer patients before and after short-term presurgical tamoxifen (ClinicalTrials.gov Identifier: NCT00738777, August 19, 2008) and cellular material was analyzed for NRF2 gene expression and immunohistochemistry. Re-sensitization of TAM-R cells to irradiation was established using pharmacological inhibition.
RESULTS: TAM-R cells exhibited decreased oxygen consumption and increased glycolysis, suggesting mitochondrial dysfunction. However, this did not explain radioresistance, as cells without mitochondria (Rho-0) were actually more radiosensitive. Real-time measurement of ROS after tamoxifen and H2O2 exposure indicated lower ROS levels and toxicity in TAM-R cells. Consistently, higher antioxidant levels were found in TAM-R cells, providing protection from irradiation-induced ROS. NRF2, a main activator of the antioxidant response, was increased in TAM-R cells and in tumor tissue of patients treated with short-term presurgical tamoxifen. NRF2 inhibition re-sensitized TAM-R cells to irradiation.
CONCLUSION: Mechanisms underlying tamoxifen-induced radioresistance are linked to cellular adaptations to persistently increased ROS levels, leading to cells with chronically upregulated antioxidant capacity and glycolysis. Pharmacological inhibition of antioxidant responses re-sensitizes breast cancer cells to irradiation.

Keywords:  Antioxidants; Breast cancer; NRF2; Radiotherapy; Reactive oxygen species; Tamoxifen

DOI:  https://doi.org/10.1186/s40170-023-00304-4
Cell Signal. 2023 Feb 07. pii: S0898-6568(23)00040-2. [Epub ahead of print] 110626

DNMT3A R882H mutation promotes acute leukemic cell survival by regulating glycolysis through the NRF2/NQO1 axis.

Xuan Chu, Liang Zhong, Wenran Dan, Xiao Wang, Zhonghui Zhang, Zhenyan Liu, Yang Lu, Xin Shao, Ziwei Zhou, Shuyu Chen, Beizhong Liu.

  BACKGROUND: Studies have confirmed that acute myeloid leukemia (AML) cells with DNA methyltransferase 3A Arg882His (DNMT3A R882H) mutation show an increased proliferation capability. However, the associated mechanism is still unclear. Glycolysis is involved in regulating malignant proliferation of cancer cell. Hence, we analyzed whether the DNMT3A R882H mutation interferes with glycolysis and thereby influences AML cell proliferation.METHODS: We generated AML cell line carrying a DNMT3A-R882H mutation and compared it with the wild type (DNMT3A-WT) with regard to glycolysis regulation. Moreover, we analyzed the cell line's proliferation and apoptosis by a CCK-8 assay, western blotting, and flow cytometry. The role of NRF2/NQO1 signaling in regulating glycolysis was investigated by NRF2-knockdown and Brusatol (specific inhibitor of NRF2) treatment.
RESULTS: DNMT3A R882H cells had a higher glucose transport capacity compared to WT cells and their viability could be reduced by glucose deprivation. Moreover, daunorubicin had a slight inhibitory effect on glycolysis while glycolysis inhibition re-sensitized mutant cells to daunorubicin. Obviously, DNMT3A R882H mutation activated the NRF2/NQO1 pathway and enhanced the glycolytic activity in mutant cells.
CONCLUSION: Taken together, these results suggest a novel mechanism by which a DNMT3A R882H mutation promotes glycolysis via activation of NRF2/NQO1 pathway. A parallel glycolysis inhibition adds to the anticancer effects of daunorubicin which might lead to a novel therapeutic approach for the treatment ofAML patients carrying a DNMT3A R882H mutation.

Keywords:  AML; DNMT3A R882H mutation; Daunorubicin; Glycolysis; NRF2/NQO1 pathway

DOI:  https://doi.org/10.1016/j.cellsig.2023.110626
Cancers (Basel). 2023 Jan 31. pii: 905. [Epub ahead of print]15(3):

SOCS1 Deficiency Promotes Hepatocellular Carcinoma via SOCS3-Dependent CDKN1A Induction and NRF2 Activation.

Md Gulam Musawwir Khan, Nadia Boufaied, Mehdi Yeganeh, Rajani Kandhi, Stephanie Petkiewicz, Ankur Sharma, Akihiko Yoshimura, Gerardo Ferbeyre, David P Labbé, Sheela Ramanathan, Subburaj Ilangumaran.

  SOCS1 deficiency, which increases susceptibility to hepatocellular carcinoma (HCC), promotes CDKN1A expression in the liver. High CDKN1A expression correlates with disease severity in many cancers. Here, we demonstrate a crucial pathogenic role of CDKN1A in diethyl nitrosamine (DEN)-induced HCC in SOCS1-deficient mice. Mechanistic studies on DEN-induced genotoxic response revealed that SOCS1-deficient hepatocytes upregulate SOCS3 expression, SOCS3 promotes p53 activation, and Cdkn1a induction that were abolished by deleting either Socs3 or Tp53. Previous reports implicate CDKN1A in promoting oxidative stress response mediated by NRF2, which is required for DEN-induced hepatocarcinogenesis. We show increased induction of NRF2 and its target genes in SOCS1-deficient livers following DEN treatment that was abrogated by the deletion of either Cdkn1a or Socs3. Loss of SOCS3 in SOCS1-deficient mice reduced the growth of DEN-induced HCC without affecting tumor incidence. In the TCGA-LIHC dataset, the SOCS1-low/SOCS3-high subgroup displayed increased CDKN1A expression, enrichment of NRF2 transcriptional signature, faster disease progression, and poor prognosis. Overall, our findings show that SOCS1 deficiency in hepatocytes promotes compensatory SOCS3 expression, p53 activation, CDKN1A induction, and NRF2 activation, which can facilitate cellular adaptation to oxidative stress and promote neoplastic growth. Thus, the NRF2 pathway represents a potential therapeutic target in SOCS1-low/SOCS3-high HCC cases.

Keywords:  CDKN1A; NRF2; SOCS1; SOCS3; TCGA-LIHC; hepatocellular carcinoma; mouse models; oxidative stress; p53

DOI:  https://doi.org/10.3390/cancers15030905
Cell Death Dis. 2023 Feb 10. 14(2): 100

UBE2E2 enhances Snail-mediated epithelial-mesenchymal transition and Nrf2-mediated antioxidant activity in ovarian cancer.

Xiaoling Hong, Ning Ma, Danjie Li, Mengwen Zhang, Wenqiuzi Dong, Jie Huang, Xinxin Ci, Songling Zhang.

Dissemination of ovarian cancer (OvCa) cells can lead to inoperable metastatic lesions in the bowel and omentum, which have a poor prognosis despite surgical and chemotherapeutical options. A better understanding of the mechanisms underlying metastasis is urgently needed. In this study, bioinformatics analyses revealed that UBE2E2, a less-studied ubiquitin (Ub)-conjugating enzyme (E2), was upregulated in OvCa and was associated with poor prognosis. Subsequently, we performed western blot analysis and IHC staining with 88 OvCa and 26 normal ovarian tissue samples, which further confirmed that UBE2E2 protein is highly expressed in OvCa tissue but weakly expressed in normal tissue. Furthermore, the silencing of UBE2E2 blocked OvCa cell migration, epithelial-mesenchymal transition (EMT) and metastasis in vitro, whereas UBE2E2 overexpression exerted the opposite effects. Mechanistically, UBE2E2 promoted p62 accumulation and increased the activity of the Nrf2-antioxidant response element (ARE) system, which ultimately activated the Snail signaling pathway by inhibiting the ubiquitin-mediated degradation of Snail. Additionally, co-IP and immunofluorescence demonstrated that a direct interaction exists between UBE2E2 and Nrf2, and the N-terminal of UBE2E2 (residues 1-52) is required and sufficient for its interaction with Nrf2 protein. Mutations in the active site cysteine (Cys139) impaired both the function and cellular distribution of UBE2E2. More importantly, the deletion of UBE2E2 reduced tumorigenicity and metastasis in xenograft OvCa mouse models. Taken together, our findings reveal the role of the UBE2E2-Nrf2-p62-Snail signaling axis in OvCa and thus provides novel therapeutic targets for the prevention of OvCa metastasis.

DOI: https://doi.org/10.1038/s41419-023-05636-z
Cells. 2023 Jan 26. pii: 418. [Epub ahead of print]12(3):

Survival Mechanisms of Metastatic Melanoma Cells: The Link between Glucocorticoids and the Nrf2-Dependent Antioxidant Defense System.

Elena Obrador, Rosario Salvador-Palmer, Rafael López-Blanch, María Oriol-Caballo, Paz Moreno-Murciano, José M Estrela.

  Circulating glucocorticoids increase during stress. Chronic stress, characterized by a sustained increase in serum levels of cortisol, has been associated in different cases with an increased risk of cancer and a worse prognosis. Glucocorticoids can promote gluconeogenesis, mobilization of amino acids, fat breakdown, and impair the body's immune response. Therefore, conditions that may favor cancer growth and the acquisition of radio- and chemo-resistance. We found that glucocorticoid receptor knockdown diminishes the antioxidant protection of murine B16-F10 (highly metastatic) melanoma cells, thus leading to a drastic decrease in their survival during interaction with the vascular endothelium. The BRAFV600E mutation is the most commonly observed in melanoma patients. Recent studies revealed that VMF/PLX40-32 (vemurafenib, a selective inhibitor of mutant BRAFV600E) increases mitochondrial respiration and reactive oxygen species (ROS) production in BRAFV600E human melanoma cell lines. Early-stage cancer cells lacking Nrf2 generate high ROS levels and exhibit a senescence-like growth arrest. Thus, it is likely that a glucocorticoid receptor antagonist (RU486) could increase the efficacy of BRAF-related therapy in BRAFV600E-mutated melanoma. In fact, during early progression of skin melanoma metastases, RU486 and VMF induced metastases regression. However, treatment at an advanced stage of growth found resistance to RU486 and VMF. This resistance was mechanistically linked to overexpression of proteins of the Bcl-2 family (Bcl-xL and Mcl-1 in different human models). Moreover, melanoma resistance was decreased if AKT and NF-κB signaling pathways were blocked. These findings highlight mechanisms by which metastatic melanoma cells adapt to survive and could help in the development of most effective therapeutic strategies.

Keywords:  Nrf2; antioxidant defense; glucocorticoids; melanoma; stress

DOI:  https://doi.org/10.3390/cells12030418
Environ Sci Pollut Res Int. 2023 Feb 11.

Flavonoids of Haloxylon salicornicum (Rimth) prevent cisplatin-induced acute kidney injury by modulating oxidative stress, inflammation, Nrf2, and SIRT1.

Shaymaa A Ramadan, Emadeldin M Kamel, Madeha A Ewais, Akef A Khowailed, Emad H M Hassanein, Ayman M Mahmoud.

  Cisplatin (CIS) is an effective chemotherapeutic drug used for the treatment of many types of cancers, but its use is associated with adverse effects. Nephrotoxicity is a serious side effect of CIS and limits its therapeutic utility. Haloxylon salicornicum is a desert shrub used traditionally in the treatment of inflammatory disorders, but neither its flavonoid content nor its protective efficacy against CIS nephrotoxicity has been investigated. In this study, seven flavonoids were isolated from H. salicornicum methanolic extract (HSE) and showed in silico binding affinity with NF-κB, Keap1, and SIRT1. The protective effect of HSE against CIS nephrotoxicity was investigated. Rats received HSE (100, 200, and 400 mg/kg) for 14 days followed by a single injection of CIS. The drug increased Kim-1, BUN, and creatinine and caused multiple histopathological changes. CIS-administered rats showed an increase in renal ROS, MDA, NO, TNF-α, IL-1β, and NF-κB p65. HSE prevented tissue injury, and diminished ROS, NF-κB, and inflammatory mediators. HSE enhanced antioxidants and Bcl-2 and downregulated pro-apoptosis markers. These effects were associated with downregulation of Keap1 and microRNA-34a, and upregulation of SIRT1 and Nrf2/HO-1 signaling. In conclusion, H. salicornicum is rich in flavonoids, and its extract prevented oxidative stress, inflammation, and kidney injury, and modulated Nrf2/HO-1 and SIRT1 signaling in CIS-treated rats.

Keywords:  Cisplatin; Haloxylon salicornicum; Nephrotoxicity; Nrf2; Oxidative stress; SIRT1

DOI:  https://doi.org/10.1007/s11356-023-25694-2
Molecules. 2023 Jan 31. pii: 1356. [Epub ahead of print]28(3):

Targeting Nrf2 and NF-κB Signaling Pathways in Cancer Prevention: The Role of Apple Phytochemicals.

Francesca Gado, Giulio Ferrario, Larissa Della Vedova, Beatrice Zoanni, Alessandra Altomare, Marina Carini, Giancarlo Aldini, Alfonsina D'Amato, Giovanna Baron.

  Plant secondary metabolites, known as phytochemicals, have recently 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. This review aims to provide a thorough overview of the main studies reported in the literature concerning apple phytochemicals, mostly polyphenols, in cancer prevention. Although there are many different mechanisms targeted by phytochemicals, the Nrf2 and NF-κB signaling pathways are the ones this review will be focused on, highlighting also the existing crosstalk between these two systems.

Keywords:  NF-κB signaling pathway; Nrf2 signaling pathway; Nrf2/NF-κB crosstalk; anti-cancer activity; apple polyphenols; circular economy; phytochemicals; secondary metabolites

DOI:  https://doi.org/10.3390/molecules28031356