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Nrf2 in Pancreatic Cancer: Comparison
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Please note this is a comparison between Version 2 by Vicky Zhou and Version 1 by Marta Cykowiak.

Pancreatic tumors are a serious health problem with a 7% mortality rate worldwide. Inflammatory processes and oxidative stress play important roles in the development of pancreatic diseases/cancer. To maintain homeostasis, a balance between free radicals and the antioxidant system is essential. Nuclear Factor Erythroid 2-Related Factor 2/NFE2L2 (Nrf2) and its negative regulator Kelch-Like ECH-Associated Protein 1 (Keap1) provide substantial protection against damage induced by oxidative stress, and a growing body of evidence points to the canonical and noncanonical Nrf2 signaling pathway as a pharmacological target in the treatment of pancreatic diseases.

  • Nrf2
  • pancreatic cancer
  • inhibitors and inducers of Nrf2

1. Dual Role of Nrf2 in Pancreatic Cancers

As mentioned previously, redox status imbalance is a common feature of various cancers types. Permanently high ROS levels in tumor cells are observed due to the oncogene activation, hypoxia, increased metabolic rates, anchorage-independent growth, and mitochondrial and/or peroxisomal dysfunction [57][1]. In these circumstances, Nrf2 plays a key role in the antioxidant response. Its function as a major regulator of redox processes can be either beneficial or prejudicial depending on the stage of tumorigenesis in pancreatic cancer cells [58][2]. In the early phase of pancreatic carcinogenesis, Nrf2 activation prevents carcinogen-induced carcinogenesis by activating the transcription of genes that regulate detoxification, antioxidation, and immune surveillance [59][3]. However, at the stage of cancer progression, the activating mutations in Nrf2 and loss-of-function mutations in Keap1 lead to the disruption of Keap1-Nrf2 binding and constitutive activation of Nrf2, increasing the expression of genes necessary for cancer cell proliferation, ferroptosis, angiogenesis, senescence, autophagy, angiogenesis, drug resistance, and metastasis [59][3]. In PDAC, gene mutations in the Keap1/Nrf2 pathway are rare, but Nrf2 expression levels are high in over 93% of pancreatic adenocarcinomas [60][4]. The Nrf2 overexpression is believed to be a consequence of the near-universal presence of oncogenic KRAS gene mutations and downstream activation of the MAPK pathway and high levels of c-Myc [61,62][5][6]. What is worth noting, the high nuclear expression of Nrf2 correlates with reduced survival rates of pancreatic cancer patients. Recently, it has also been found that elevated Nrf2 levels in early precursor lesions in the pancreas contribute to pancreatic carcinogenesis [63,64][7][8]. Thus, in the next section, we give a comprehensive overview of the dual roles of the Keap1-Nrf2 pathway in pancreatic cancer.

1.1. Nrf2 as Tumor Suppressor in Pancreatic Cancer

During the early stage of pancreatic carcinogenesis, Nrf2 exerts a tumor-suppressive role by binding to antioxidant response elements and activating its downstream target genes (such as NQO1, SOD1, HO-1, ATF3, IL-17D, and SQSTM1/p62) that regulate the cellular antioxidant/detoxification response, immune surveillance, and autophagy [65,66,67,68][9][10][11][12]. Evidence showing the preventive effects of Nrf2 on pancreatic carcinogenesis and pancreatic tumor growth and metastasis has previously been provided. Kim et al. showed that the activation of Nrf2, caused by oxidative stress, protected pancreatic beta cells from damage and apoptosis, preventing pancreatic carcinogenesis induced by oxidants and carcinogens [69][13]. Furthermore, the Nrf2 activation by various natural products has also been found to inhibit pancreatic cancer growth and induce apoptosis, although the exact association of the activation of Nrf2 and the anticancer efficacy need to be further investigated [70,71][14][15]. Probst et al., found that RTA 405, an antioxidant inflammation modulator and Nrf2 activator, suppresses cancer cell survival and promotes apoptosis via downregulating the NF-κB activity [72][16]. In the next section, we present the exact results of studies using Nrf2 activators.

1.2. The Carcinogenic Role of Keap1-Nrf2 Pathway in Pancreatic Cancer

In contrast to the protective impact of Nrf2 on oxidative stress-induced carcinogenesis, a great number of studies have demonstrated a supporting role of the Keap1-Nrf2 pathway in pancreatic cancer development. It is widely accepted that Kras-mediated Nrf2 expression and activation leads to low intracellular ROS levels and promotes pancreatic tumorigenesis and metastasis, whereas Nrf2 inhibition blocks Kras-induced cell proliferation, tumorigenesis, and metastasis. Hamada et al. examined the role of Nrf2 in pancreatic carcinogenesis in a mouse model carrying pancreas-specific Kras and p53 mutations (KPC mouse model) [63][7]. They demonstrated that Nrf2 deletion in the KPC mice correlated with a decrease in the formation of precancerous lesions and reduced the development of invasive pancreatic cancer. Furthermore, two cell lines lacking the expression of Nrf2 (KPCN) and its downstream target genes, including NQO1, have been established. KPCN-derived cell lines revealed increased sensitivity to oxidative stress and chemotherapeutic agent. Interestingly, the simultaneous activation of Kras and Nrf2 by Kras mutation and Keap1 deletion, respectively, did not promote pancreatic cancer development but led to pancreatic atrophy [73][17].
An important aspect of the activation of Nrf2 in pancreatic cancer is chemoresistance [81][18]. The Keap1-Nrf2 pathway is involved in pancreatic cancer chemoresistance by regulating the expression of drug resistance-associated genes (MRP1, MRP2, MRP3, MRP4, MRP5, and ABCG2) [68,82,83][12][19][20] and previously mentioned cytoprotective antioxidant genes. Moreover, Duong et al. observed that upregulation of aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and aldehyde dehydrogenase 3 family, member A1 (ALDH3A1) caused by Nrf2 may also contribute to drug resistance in pancreatic cancers [84][21]. Nevertheless, chemotherapies themselves, e.g., gemcitabine have been found to increase Nrf2 expression. This effect was inhibited by pretreatment with Nrf2 inhibitors, thus enhancing the sensitivity of pancreatic cancer cells to chemotherapy [85][22]. With reference to the abovementioned mechanisms, in the next section we present the selected Nrf2 inhibitors in pancreatic cancer therapies.

2. Therapeutic Strategies Targeting Nrf2 in Pancreatic Cancers

Natural compounds derived from medicinal plants have been known to possess therapeutic properties for many years and have been employed to successfully treat a great variety of human disorders. Recently, many plant extracts and discrete phytochemicals have emerged as promising chemopreventive and anticancer agents. Currently, many of them are under clinical trial investigation or already being administered in established therapeutic regimens. Extensive research has been pursued with a view to finding natural compounds as well as synthetic compounds with modulatory properties on Nrf2, known to be often overexpressed in many types of cancers, including pancreatic cancers. In the next section, we focus on some of the most recent and significant discoveries in pancreatic cancer therapies targeting Nrf2. We summarized them in the Table 1.
Table 1.
Therapeutic strategies targeting Nrf2 in pancreatic cancers.
Natural Compounds
Compound Dosage Model Mechanism of Modulation Reference
Trigonelline 0.01–10 μM Panc1, MiaPaCa-2, and Colo357 cell lines a dose-dependent inhibition of ARE-driven luciferase expression; a decreased accumulation of Nrf2 protein in the nucleus; reduction of proteasome activity [86][23]
Brusatol 0.5 μM PATU-8988, BxPC-3 and Panc1 cell lines inhibition of the Nrf2 pathway and increased ROS accumulation; abrogation of Gemcitabine-induced Nrf2 activation; decrease in mRNA and protein levels of Nrf2 target genes [89][24]
2 mg/kg i.p. once/day Panc-1 xenografts augmented antitumor activity of Gemcitabine [90][25]
Digoxin 20 and 40 and 80 nM SW1990 and Panc1 cell lines with induced gemcitabine-resistance decrease in total and nuclear protein levels of Nrf2; an increase in the sensitivity to gemcitabine; an increase in the number of cells undergoing apoptosis and inhibition of cell colony formation compared with gemcitabine single treatment [92][26]
Ailanthone 0.1–2 μg/mL Panc1 cell line post-translational downregulation of Nrf2 and YAP proteins, by targeting deubiquitinases [95][27]
Curcumin   Panc1 and CFPAC-1 cell lines enhanced antitumor effect of Sestrin2 through the Nrf-2-Keap1/HO-1/NQO-1 signaling pathway [96][28]
Meriva®, a patented preparation of curcumin complexed with phospholipids clinical trials; fifty-two consecutive patients activation of Nrf2 downregulates NF-κB controlled genes involved in inflammation, proliferation, survival, invasion, angiogenesis, and metastasis [97][29]
Sulforaphane 1–100 μM Panc1 and MiaPaCa-2 cell lines activation of adenosine 5′-monophosphate-activated protein kinase (AMPK) by excessively generated reactive oxygen species and subsequent increase in the Nrf2 nuclear translocation, which suppresses pancreatic cancer cell proliferation [99][30]
50 mg/kg, i.p. transgenic mouse model inhibition of tumor growth, consistent with the antiproliferative effects of SFN through ROS activated AMPK signaling pathway and NRF2 nuclear translocation [99][30]
Esculetin 100 μM Panc1, MiaPaCa-2, and AsPC-1 cells directly binding to Keap1 and inhibition of its binding to Nrf2; reduction of ROS level, inhibition of cell growth, cell cycle arrest at G1 phase, and induction of apoptosis and loss of mitochondrial membrane potential [100][31]
Xanthohumol 5 and 10 μM Panc1 enhanced binding of Nrf2 to ARE sequence and increased protein level of Nrf2 correlated with decreased NF-κB expression;

protein levels and inhibited proliferation		 [71][15]
5 and 10 μM MiaPaCa-2 cell line enhanced binding of Nrf2 to ARE sequence and increased protein level of Nrf2;

in the combination with PEITC increased Caspase-3 and LC3 protein levels and inhibition of proliferation		 [70][14]
Resveratrol 50 and 100 μM Panc1 and MiaPaCa-2 cell lines reduction in the level of NAF-1 and enhancement of the Nrf2 expression by inducing the accumulation of ROS, which contribute to cell death [102][32]
5 and 10 μM Panc1 and MiaPaCa-2 cell lines promotion of apoptosis via activation of Nrf2 and consequently downregulation of NF-κB [70,71][14][15]
Phenethyl isothiocyanate 5 μmol/L Panc-28, MiaPaCa-2, AsPC-1 cell lines depletion of cellular GSH [103][33]
5 and 10 μM MiaPaCa-2 cell line activation of Nrf2 and its target genes by increased levels of p-JNK and decreased levels of p-GSK3β; increased Caspase-3 and LC3 protein levels [70][14]
Synthetic compounds
Compound Dosage Model Mechanism of modulation Reference
Dexamethasone 1 µM Panc1 CSLC and PSN-1 CSLC

(CSLC-cancer stem-like cells)		 reduction of Nrf2 expression with significant decrease in GSH; increase in the growth-inhibitory effects of Gemcitabine and 5-fluorouracil [104][34]
Dimethyl Fumarate 100 μM MiaPaCa-2 cell line a decrease in total Nrf2 and HO-1 corresponding with decreased DJ-1 protein levels [107][35]
PIK-75 0.1–1 μM MiaPaCa-2 and AsPC-1 cell lines; xenograft model reduction of the Nrf2 protein levels and its transcriptional activity by proteasome-mediated degradation [82][19]
NSC84167 1–10 μM Panc1 and AsPC-1 cell lines; patient-derived pancreatic cancer cells and PDX tumor tissue selectively targeting Nrf2-activated pancreatic cancer by inhibiting asparagine synthesis pathway; induction of apoptosis in Nrf2-activated pancreatic cancer cells independent of ROS [60][4]

3. Conclusions

The role of oxidative stress and inflammation in pancreatic cancer development is well established. Due to the complex pathophysiology of pancreatic cancer, there is currently no effective treatment to counteract this damage. The dual role of Nrf2 in pancreatic cancer development, as well as its overexpression in pancreatic cancer, can be considered as a potential therapeutic target. The confirmation of this thesis has been found in the articles from the last decade.
It is now known that natural and/or synthetic compounds such as brusatol, curcumin, sulforaphane, and NSC84167 exert their effects by modulating the Nrf2 pathway. However, further elucidation of the detailed mechanism of molecular modifications by these compounds with respect to pancreatic cancer still needs to be found.
In summary, further research involving the use of inhibitors to block Nrf2 activity in malignant pancreatic tumors with constitutively active Nrf2 would be an important treatment strategy, and the use of human samples such as human biopsies or 3D cultures (organoids) can help develop new treatment strategies for this disease.

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