Role of Nrf2 in Pancreatic Cancer

Cykowiak, Marta; Krajka‐Kuźniak, Violetta

doi:10.3390/antiox11010098

Cited by 18 publications

(13 citation statements)

References 110 publications

(133 reference statements)

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“…In addition, Nrf2 expression level was high in more than 93% of pancreatic adenocarcinomas (Dai et al, 2021). Nrf2 overexpression is thought to be the result of the almost universal oncogenic KRAS gene mutation and downstream activation of the MAPK pathway as well as high levels of c-Myc (Cykowiak and Krajka-Kuźniak, 2021). Notably, high nuclear expression of Nrf2 is associated with reduced survival in patients with pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Wogonin induces ferroptosis in pancreatic cancer cells by inhibiting the Nrf2/GPX4 axis

et al. 2023

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Pancreatic cancer is a common gastrointestinal tract malignancy. Currently, the therapeutic strategies for pancreatic cancers include surgery, radiotherapy, and chemotherapy; however, the surgical procedure is invasive, and the overall curative outcomes are poor. Furthermore, pancreatic cancers are usually asymptomatic during early stages and have a high degree of malignancy, along with a high rate of recurrence and metastasis, thereby increasing the risk of mortality. Studies have shown that ferroptosis regulates cell proliferation and tumour growth and reduces drug resistance. Hence, ferroptosis could play a role in preventing and treating cancers. Wogonin is a flavonoid with anticancer activity against various cancers, including pancreatic cancer. It is extracted from the root of Scutellaria baicalensis Georgi. In this study, we show that wogonin inhibits the survival and proliferation of human pancreatic cancer cell lines and induces cell death. We performed RNA-sequencing and analysed the differentially expressed gene and potential molecular mechanism to determine if wogonin reduced cell survival via ferroptosis. Our results showed that wogonin upregulates the levels of Fe2+, lipid peroxidation and superoxide and decreases the protein expression levels of ferroptosis suppressor genes, and downregulates level of glutathione in pancreatic cancer cells. In addition, ferroptosis inhibitors rescue the ferroptosis-related events induced by wogonin, thereby confirming the role of ferroptosis. A significant increase in ferroptosis-related events was observed after treatment with both wogonin and ferroptosis inducer. These results show that wogonin could significantly reduces pancreatic cancer cell proliferation and induce ferroptosis via the Nrf2/GPX4 axis. Therefore, wogonin could be potentially used for treating patients with pancreatic cancer.

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Section: Introductionmentioning

confidence: 99%

Wogonin induces ferroptosis in pancreatic cancer cells by inhibiting the Nrf2/GPX4 axis

et al. 2023

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“…While NRF2 is accepted as the master of oxidative/electrophilic stress responses, the literature points to roles for NRF2 in multiple biological processes [ 19 , 20 ]. Its clinical relevance in cancer biology and treatment is shown by NRF2 being dysregulated in many human cancers [ 21 , 22 , 23 , 24 , 25 ], especially where activating mutations, deletions, or gene amplifications affect NRF2/KEAP1 function to promote constitutive Nrf2 expression [ 15 , 26 ], with increased therapeutic resistance and poor outcomes [ 21 , 22 , 23 , 24 , 25 ]. The close communication between the NRF2/KEAP1 partners is nicely illustrated by their mutually exclusive mutation patterns in head and neck [ 27 ] and lung cancer [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

NRF2 Mediates Cellular Resistance to Transformation, Radiation, and Inflammation in Mice

Schaue

Micewicz²,

Ratikan

et al. 2022

Antioxidants

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Nuclear factor erythroid 2-related factor 2 (NRF2) is recognized as a master transcription factor that regulates expression of numerous detoxifying and antioxidant cytoprotective genes. In fact, models of NRF2 deficiency indicate roles not only in redox regulation, but also in metabolism, inflammatory/autoimmune disease, cancer, and radioresistancy. Since ionizing radiation (IR) generates reactive oxygen species (ROS), it is not surprising it activates NRF2 pathways. However, unexpectedly, activation is often delayed for many days after the initial ROS burst. Here, we demonstrate that, as assayed by γ-H2AX staining, rapid DNA double strand break (DSB) formation by IR in primary mouse Nrf2–/– MEFs was not affected by loss of NRF2, and neither was DSB repair to any great extent. In spite of this, basal and IR-induced transformation was greatly enhanced, suggesting that NRF2 protects against late IR-induced genomic instability, at least in murine MEFs. Another possible IR- and NRF2-related event that could be altered is inflammation and NRF2 deficiency increased IR-induced NF-κB pro-inflammatory responses mostly late after exposure. The proclivity of NRF2 to restrain inflammation is also reflected in the reprogramming of tumor antigen-specific lymphocyte responses in mice where Nrf2 k.o. switches Th2 responses to Th1 polarity. Delayed NRF2 responses to IR may be critical for the immune transition from prooxidant inflammation to antioxidant healing as well as in driving cellular radioresistance and survival. Targeting NRF2 to reprogram immunity could be of considerable therapeutic benefit in radiation and immunotherapy.

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“…Several authors reported that P38-MAPK signaling is enhanced during development of AP, and the inhibition of this pathway is associated with alleviation of its symptoms (Ma et al 2018;Hu et al 2019; Morsy and Ahmed 2020). Furthermore, An et al (Cykowiak and Krajka-Kuźniak 2022) reported that OS may increase P38-MAPK signaling, whereas a study performed by Hu et al 41 revealed that enhancement of the activity of this pathway is associated with decreased levels of endogenous antioxidants (SOD, GSH). These data indicate that OS may enhance P38-MAPK signaling pathway, which subsequently results in diminishing the antioxidative defense, leading to development of positive feedback loop.…”

Section: Mapk Pathwaymentioning

confidence: 99%

“…In an early stage of carcinogenesis, diminished expression of Nrf2 increases ROS-driven DNA alteration, thus facilitating cancer development. However, during progression of PDAC, the high expression of Nrf2 is associated with increased cancer cell survival, resulting in enhanced cancer growth (Cykowiak and Krajka-Kuźniak 2022). Given that CP predisposes to PDAC (Hao et al 2017), downregulation of Nrf2 expression in CP may be an essential step during progression from chronic inflammation to neoplasm.…”

Section: Keap1/nrf2/are Pathwaymentioning

confidence: 99%

Putative molecular targets for vitamin A in neutralizing oxidative stress in acute and chronic pancreatitis — a systematic review

Burzyński

Fichna

Tarasiuk

2023

Naunyn-Schmiedeberg's Arch Pharmacol

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Acute pancreatitis (AP) and chronic pancreatitis (CP) are debilitating diseases of gastrointestinal tract and constitute great threat for human health in high-income countries. Recent studies emphasize the impact of oxidative stress on development of these pathologies, and numerous authors evaluate the effect of the antioxidant therapy on the course of AP and CP. Though several antioxidative agents were discovered in the past decades, vitamins remain canonical antioxidants. Despite the fact that vitamin A is known for its antioxidative effect, there is little data about the impact of vitamin A on oxidative stress in the pathogenesis of AP and CP. The scope of the review is to evaluate molecular targets for vitamin A, which may be involved in oxidative stress occurring in the course of AP and CP. Our research of available literature revealed that several mechanisms are responsible for attenuation of oxidative stress in AP and CP, including Nrf2, MAPK, AMPK, TLR3, and TLR4. Furthermore, these factors are at least partially expressed in vitamin A-dependent manner, though further investigations are required for elucidating in detail the role of vitamin A in defense against reactive oxygen species. Our review revealed that vitamin A might influence the expression of several molecular pathways involved in antioxidative defense and cytoprotection; thus, its administration during AP and CP may change the course of the disease.

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Role of Nrf2 in Pancreatic Cancer

Cited by 18 publications

References 110 publications

Wogonin induces ferroptosis in pancreatic cancer cells by inhibiting the Nrf2/GPX4 axis

Wogonin induces ferroptosis in pancreatic cancer cells by inhibiting the Nrf2/GPX4 axis

NRF2 Mediates Cellular Resistance to Transformation, Radiation, and Inflammation in Mice

Putative molecular targets for vitamin A in neutralizing oxidative stress in acute and chronic pancreatitis — a systematic review

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