Perspectives of the Nrf-2 signaling pathway in cancer progression and therapy

Basak, Priyanka; Sadhukhan, Pritam; Sarkar, Poulami; Sil, Parames C.

doi:10.1016/j.toxrep.2017.06.002

Cited by 114 publications

(94 citation statements)

References 194 publications

(227 reference statements)

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“…In addition to the above Keap1‐dependent mechanism, there is also evidence showing that Nrf2 can be regulated independently of Keap1, as follows: a) Nrf2 transcriptional regulation and self‐regulation. Nrf2 binding to its own promoter region directly to increase self‐regulation . b) Posttranscriptional regulation.…”

Section: The Keap1‐nrf2/are Signaling Pathway and Its Regulationmentioning

confidence: 99%

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Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

Zhou

Jiang

et al. 2019

Chemistry & Biodiversity

136

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The Keap1‐Nrf2/ARE signaling pathway is an important defense system against exogenous and endogenous oxidative stress injury. The dysregulation of the signaling pathway is associated with many diseases, such as cancer, diabetes, and respiratory diseases. Over the years, a wide range of natural products has provided sufficient resources for the discovery of potential therapeutic drugs. Among them, polyphenols possess Nrf2 activation, not only inhibit the production of ROS, inhibit Keap1‐Nrf2 protein–protein interaction, but also degrade Keap1 and regulate the Nrf2 related pathway. In fact, with the continuous improvement of natural polyphenols separation and purification technology and further studies on the Keap1‐Nrf2 molecular mechanism, more and more natural polyphenols monomer components of Nrf2 activators have been gradually discovered. In this view, we summarize the research status of natural polyphenols that have been found with apparent Nrf2 activation and their action modes. On the whole, this review may guide the design of novel Keap1‐Nrf2 activator.

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Section: The Keap1‐nrf2/are Signaling Pathway and Its Regulationmentioning

confidence: 99%

“…Nrf2 binding to its own promoter region directly to increase self-regulation. [25] b) Posttranscriptional regulation. miR-144, miR-27a, miR-142-5p, miR-153, and miR-28, can negatively regulate the Keap1/Nrf2 system in a Keap1-independent mechanism.…”

Section: Modulation Mechanism Keap1-nrf2/are Signaling Pathwaymentioning

confidence: 99%

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

Zhou

Jiang

et al. 2019

Chemistry & Biodiversity

136

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“…17,42,43 Potential treatment options addressing oxidative stress related pathways involving NRF2, AKR1C and PI3K upregulation were recently discussed. [44][45][46] However, due to the high expression of AKR1C enzymes in normal tissues like liver and pancreas, it will be important to investigate potential adverse events of these drugs in these tissues.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV‐negative tumors is an indicator of poor prognosis

Huebbers

Verhees

Poluschkin

et al. 2019

Intl Journal of Cancer

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Different studies have shown that HPV16‐positive OPSCC can be subdivided based on integration status (integrated, episomal and mixed forms). Because we showed that integration neither affects the levels of viral genes, nor those of virally disrupted human genes, a genome‐wide screen was performed to identify human genes which expression is influenced by viral integration and have clinical relevance. Thirty‐three fresh‐frozen HPV‐16 positive OPSCC samples with known integration status were analyzed by mRNA expression profiling. Among the genes of interest, Aldo‐keto‐reductases 1C1 and 1C3 (AKR1C1, AKR1C3) were upregulated in tumors with viral integration. Additionally, 141 OPSCC, including 48 HPV‐positive cases, were used to validate protein expression by immunohistochemistry. Results were correlated with clinical and histopathological data. Non‐hierarchical clustering resulted in two main groups differing in mRNA expression patterns, which interestingly corresponded with viral integration status. In OPSCC with integrated viral DNA, often metabolic pathways were deregulated with frequent upregulation of AKR1C1 and AKR1C3 transcripts. Survival analysis of 141 additionally immunostained OPSCC showed unfavorable survival rates for tumors with upregulation of AKR1C1 or AKR1C3 (both p <0.0001), both in HPV‐positive (p ≤0.001) and ‐negative (p ≤0.017) tumors. OPSCC with integrated HPV16 show upregulation of AKR1C1 and AKR1C3 expression, which strongly correlates with poor survival rates. Also in HPV‐negative tumors, upregulation of these proteins correlates with unfavorable outcome. Deregulated AKR1C expression has also been observed in other tumors, making these genes promising candidates to indicate prognosis. In addition, the availability of inhibitors of these gene products may be utilized for drug treatment.

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“…According to our data, MSC operate on ER stress mainly via PERK‐Nrf2 pathway. Nrf2 is known to be an important inducer of cellular defence enzymes and to target various genes that participate in stress‐related processes including antioxidation, detoxification, anti‐inflammation, metabolism, cell proliferation and differentiation . ER stress is associated with high levels of oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

“…Nrf2 is known to be an important inducer of cellular defence enzymes and to target various genes that participate in stress-related processes including antioxidation, detoxification, anti-inflammation, metabolism, cell proliferation and differentiation. 26,27 ER stress is associated with high levels of oxidative stress. Stimulation of MSC with adrenaline has been shown to increase cellular glutathione (GSH) levels, a critical thiol antioxidant associated with the pathogenesis of IPF, via a process involving Nrf2-mediated activation of the CySS/glutamate pathway.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells reduce ER stress via PERK‐Nrf2 pathway in an aged mouse model

et al. 2019

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Background and objective Mesenchymal stem cells (MSC) have been shown to ameliorate the deleterious effects of bleomycin in murine models. However, the mechanism responsible for protection from pulmonary fibrosis by stem cell therapy is still poorly understood, especially in terms of endoplasmic reticulum (ER) stress. We hypothesized that during bleomycin‐induced lung injury, markers of ER stress, specifically the activation of the unfolded protein response (UPR), increase during injury, resembling the kinetics of collagen deposition in the lung described for the bleomycin model. We aimed to elucidate the possible role of MSC in ER stress modulation. Methods To determine the kinetics of ER stress in aged mice, the expression of ER stress markers after bleomycin lung injury was measured in old mice at different time points (days 0, 3, 7, 14 and 21). To evaluate the consequences of systemic delivery of MSC on lung ER stress in the bleomycin model, we evaluated changes in body weight, lung histology and protein expression of ER stress markers. Results The level of expression of UPR transcription factor XBP‐1 and its regulator BiP was elevated at day 7 and progressively increased up to day 21. MSC inhibited BiP expression in bleomycin‐induced ER stress, attenuating ER stress via the protein kinase RNA‐like ER kinase (PERK)‐Nrf2 pathway. The expression levels of other ER stress markers were not perturbed by MSC. Conclusion Our data suggest that MSC operate on ER stress via several pathways, but the PERK‐Nrf2 pathway revealed to be the main functioning pathway in our bleomycin model.

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Perspectives of the Nrf-2 signaling pathway in cancer progression and therapy

Cited by 114 publications

References 194 publications

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

Recent Advances of Natural Polyphenols Activators for Keap1‐Nrf2 Signaling Pathway

Upregulation of AKR1C1 and AKR1C3 expression in OPSCC with integrated HPV16 and HPV‐negative tumors is an indicator of poor prognosis

Mesenchymal stem cells reduce ER stress via PERK‐Nrf2 pathway in an aged mouse model

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