Effects of <i>Nrf2</i> silencing on oxidative stress‐associated intestinal carcinogenesis in mice

Yokoo, Yuh; Kijima, Aki; Ishii, Yuji; Takasu, Shinji; Tsuchiya, Takuma; Umemura, Takashi

doi:10.1002/cam4.672

Cited by 28 publications

(24 citation statements)

References 28 publications

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“…This in turn results in greater risk of CRC [35]. Other authors have observed similar results when NRF2 is overexpressed as a consequence of silencing, or as a result of epigenetic changes in this gene [36–38, 51]. Another way to induce overexpression of NRF2 is using chemical compounds.…”

Section: Discussionmentioning

confidence: 88%

The NRF2 transcription factor plays a dual role in colorectal cancer: A systematic review

et al. 2017

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BackgroundColorectal cancer is one of the most common cancers worldwide, and is influenced by the interplay of various factors, including a very strong genetic component. For instance, incorrect mitochondrial biogenesis is correlated with increased risk of developing colorectal cancer. Thus, it is important to understand the consequences of changes in both the expression and the correct function of the transcription factors that regulate mitochondrial biogenesis, namely NRF2.ObjectivesThe main objective of this paper is to characterise the relationship between NRF2 and colorectal cancer by compiling data from an exhaustive literature search.MethodsInformation was obtained by defining specific search terms and searching in several databases. After a strict selection procedure, data were tabulated and the relationships between articles were assessed by measuring heterogeneity and by constructing conceptual maps.Results and discussionWe found a general consensus in the literature that the presence of oxidizing agents as well as the inhibition of the NRF2 repressor Keap1 maintain NRF2 expression at basal levels. This predominantly exerts a cytoprotective effect on cells and decreases risk of colorectal cancer. However, if NRF2 is inhibited, protection against external agents disappears and risk of colorectal cancer increases. Interestingly, colorectal cancer risk is also increased when NRF2 becomes overexpressed. In this case, the increased risk arises from NRF2-induced inflammation and resistance to chemotherapy.ConclusionThe proper basal function of NRF2 and Keap1 are essential for preventing oncogenic processes in the colon. Consequently, any disruption to the expression of these genes can promote the genesis and progression of colon cancer.

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Section: Discussionmentioning

confidence: 88%

The NRF2 transcription factor plays a dual role in colorectal cancer: A systematic review

et al. 2017

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“…Moreover, treatment with a specific HO-1 inhibitor, ZnPP, reversed the cytoprotective effect of PS under H 2 O 2 -induced oxidative stress, indicating that Nrf2-mediated HO-1 activation is an important route for the cytoprotective activity of PS in H 2 O 2 -treated HaCaT keratinocytes. In addition, Nrf2-deficient mice (Nrf2 -/-) are associated with higher sensitivity to carcinogenesis [35] and are linked with the enhanced metastasis of cancer cells [36], which indicated that Nrf2/HO-1 also attenuated carcinogenesis and the metastasis of cancer cells. Thus, boosting Nrf2/HO-1 activity is a promising target for the treatment of inflammation and cancer.…”

Section: Discussionmentioning

confidence: 99%

Anthocyanins from Hibiscus syriacus L. Inhibit Oxidative Stress-Mediated Apoptosis by Activating the Nrf2/HO-1 Signaling Pathway

et al. 2020

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Hibiscus syriacus L. is distributed widely throughout Eastern and Southern Asia and considered as the national flower of South Korea. The extraction of several plant parts of H. syriacus L. is currently used as a natural remedy for several diseases, including breast and lung cancer, microbial infection, and chronic inflammation. However, the effect of the anthocyanin extract of H. syriacus L. petals (PS) in oxidative stress conditions has not been studied. In this study, we evaluated the cytoprotective effect of PS against H2O2-induced oxidative stress in HaCaT keratinocytes. In this study, we found that PS significantly inhibited H2O2-induced apoptosis of HaCaT keratinocytes. We also revealed that PS mediated-cytoprotective effect was associated with the increased expression of heme oxygenase-1 (HO-1) arising from the activation of nuclear factor erythroid 2-related factor-2 (Nrf2). PS also decreased H2O2-induced excessive intracellular ROS generation and restored H2O2-induced mitochondrial depolarization through the downregulation of mitochondrial ROS production. Furthermore, H2O2-induced Bax and caspase-3 expression was markedly abolished in the presence of PS. The inhibition of HO-1 by zinc protoporphyrin significantly attenuated the cytoprotective effect of PS in H2O2-treated HaCaT keratinocytes along with ROS generation, indicating that HO-1 crucially affects PS-mediated cytoprotective properties. Collectively, our results suggested that, under H2O2-mediated oxidative stress conditions, PS sustained a normal level of mitochondrial membrane potential and ROS generation in HaCaT keratinocytes by activating the Nrf2/HO-1 axis, exerting cytoprotective effects against oxidative stress.

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“…Nrf2 is generally considered as a primary defence mechanism of the cell and a major regulator of cell survival. Nrf2 deficient mice are more susceptible to carcinogenesis 54,55 . Many have reported the chemopreventive effect of Nrf2 in cancer [56][57][58] .…”

Section: Discussionmentioning

confidence: 99%

Antioxidant effects of sulforaphane in human HepG2 cells and immortalised hepatocytes

Liu

Wang

Tang

et al. 2019

Food and Chemical Toxicology

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Sulforaphane (SFN) has shown anti-cancer effects in cellular and animal studies but its effectiveness has been limited in human studies. Here, the effects of SFN were measured in both human hepatocyte (HHL5) and hepatoma (HepG2) cells. Results showed that SFN inhibited cell viability and induced DNA strand breaks at high doses (≥ 20 µM). It also activated the nuclear factor (erythroidderived 2)-like 2 (Nrf2), and increased intracellular glutathione (GSH) levels at 24 hours. Pretreatment with a low dose SFN (≤5 µM) protected against hydrogen peroxide (H 2 O 2)-induced cell damage. High doses of SFN were more toxic towards HHL5 compared to HepG2 cells; the difference is likely due to the disparity in the responses of Nrf2-driven enzymes and-GSH levels between the two cell lines. In addition, HepG2 cells hijacked the cytoprotective effect of SFN over a wider dose range (1.25-20 µM) compared to HHL5. Manipulation of levels of GSH and Nrf2 in HepG2 cells confirmed that both molecules mediate the protective effects of SFN against H 2 O 2. The non-specific nature of SFN in the regulation of cell death and survival could present undesirable risks, i.e. be more toxic to normal cells, and cause chemo-resistance in tumor cells. These issues should be addressed in the context for cancer prevention and treatment before large scale clinical trials are undertaken.

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Effects of Nrf2 silencing on oxidative stress‐associated intestinal carcinogenesis in mice

Cited by 28 publications

References 28 publications

The NRF2 transcription factor plays a dual role in colorectal cancer: A systematic review

The NRF2 transcription factor plays a dual role in colorectal cancer: A systematic review

Anthocyanins from Hibiscus syriacus L. Inhibit Oxidative Stress-Mediated Apoptosis by Activating the Nrf2/HO-1 Signaling Pathway

Antioxidant effects of sulforaphane in human HepG2 cells and immortalised hepatocytes

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