Contradictory roles of Nrf2/Keap1 signaling pathway in cancer prevention/promotion and chemoresistance

Jeddi, Farhad; Soozangar, Narges; Sadeghi, Mohammad Reza; Somi, Mohammad Hossein; Samadi, Nasser

doi:10.1016/j.dnarep.2017.03.008

Cited by 78 publications

(50 citation statements)

References 180 publications

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“…It has also been shown that Nrf2 overexpression has a vital function in the pathogenesis of CRC. Nrf2 up-regulation has also been shown in various tumors including gastric, lung, breast, liver, and endometrium tumors tissues [40,41]. Nrf2 through induction of antioxidant transcription in pancreatic cancer promoted gemcitabine resistance [42].…”

Section: Discussionmentioning

confidence: 99%

The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

Payandeh¹,

Tazehkand²,

Mansoori³

et al. 2020

Preprint

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Background: Nuclear factor−erythroid 2−related factor 2 (Nrf2) has a key function in promoting chemoresistance in various cancers. PD-L1 is one of the downstream targets of Nrf2 signaling pathway, having some beneficial impacts on tumors growth by inhibition of the immune system. The aim of this study was to investigate the potential role of Nrf2- PD- L1 axis in the promotion of oxaliplatin resistance in colon cancer cells. Result: Our data revealed that Nrf2 and PD-L1 mRNA expressions were markedly higher in tumor tissues compared to margin tissues. PD-L1 mRNA expression level was also increased in the resistant cells. However, Nrf2 expression was decreased and increased in SW480/Res and LS174T/Res cells, respectively. Nrf2 inhibition through siRNA in SW480/Res and LS174T/Res decreased the IC50 values of oxaliplatin. Inhibition of Nrf2 significantly increased oxaliplatin-induced apoptosis and reduced migration in SW480/Res cells when accompanied with oxaliplatin. Conclusion: Our study suggests that effective inhibition of Nrf2/PD-L1 signaling pathways can be considered as a novel approach to improve oxaliplatin efficacy in colon cancer patients.

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Section: Discussionmentioning

confidence: 99%

The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

Payandeh¹,

Tazehkand²,

Mansoori³

et al. 2020

Preprint

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“…Moreover, it has been established that PD‐1/PD‐L1 dependent pathways are involved in the pathogenesis of CRC (Cortez et al, 2016). Nrf2/Keap1 is reported to be one of the signaling pathways involved in CRC initiation and progression (Jeddi, Soozangar, Sadeghi, Somi, & Samadi, 2017). Zhu et al (2018) have shown that Nrf2 functions as an upstream transcriptional activator of PD‐L1.…”

Section: Introductionmentioning

confidence: 99%

PD‐1/PD‐L1‐dependent immune response in colorectal cancer

Payandeh

Khalili

Somi

et al. 2020

Journal Cellular Physiology

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110

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Colorectal cancer (CRC) is still considered as the third most frequent cancer in the world. Microsatellite instability (MSI), inflammation, and microRNAs have been demonstrated as the main contributing factors in CRC. Subtype 1 CRC is defined by NK cells infiltration, induction of Th1 lymphocyte and cytotoxic T cell responses as well as upregulation of immune checkpoint proteins including programmed cell death‐1 (PD‐1). Based on the diverse features of CRC, such as the stage and localization of the tumor, several treatment approaches are available. However, the efficiency of these treatments may be decreased due to the development of diverse resistance mechanisms. It has been proven that monoclonal antibodies (mAbs) can increase the effectiveness of CRC treatments. Nowadays, several mAbs including nivolumab and pembrolizumab have been approved for the treatment of CRC. Immune checkpoint receptors including PD‐1 can be inhibited by these antibodies. Combination therapy gives an opportunity for advanced treatment for CRC patients. In this review, an update has been provided on the molecular mechanisms involved in MSI colorectal cancer immune microenvironment by focusing on PD‐ligand 1 (PD‐L1) and treatment of patients with advanced immunotherapy, which were examined in the different clinical trial phases. Considering induced expression of PD‐L1 by conventional chemotherapeutics, we have summarized the role of PD‐L1 in CRC, the chemotherapy effects on the PD‐1/PD‐L1 axis and novel combined approaches to enhance immunotherapy of CRC by focusing on PD‐L1.

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“…The mechanism by which Nrf2 promotes cancer cell formation and progression includes inhibition of apoptosis, induction of detoxification enzymes, and expression of antioxidative stress genes [33]. The activation of cell protective factors downstream of Nrf2 is conducive to the survival of cancer cells and resistance of cancer cells to chemotherapy [34]. It has been reported that Nrf2 is involved in the expression of antiapoptotic proteins, promotes chemotherapy tolerance of liver cancer, and is associated with the expression of Bcl-xl, an antiapoptotic gene [35].…”

Section: Discussionmentioning

confidence: 99%

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. Methods. We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α interacts with SET8. In vivo experiments were performed to verify the conclusions from the in vitro experiments. Results. Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro and in vivo results demonstrated that fasting decreased cell viability and downregulated expression of SET8, Nrf2, and downstream effectors of Nrf2, while it upregulated Keap1 expression, mediated ROS accumulation, and induced HCC cell apoptosis. These results were similar to what is observed in SET8-deficient cells. Furthermore, SET8 was found to interact with PGC1α, and both PGC1α and H4K20me1, a downstream target of SET8, were found to be enriched at the Keap1 promoter region. These two factors were further determined to attenuate Keap1 promoter activity. Conclusions. The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.

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Contradictory roles of Nrf2/Keap1 signaling pathway in cancer prevention/promotion and chemoresistance

Cited by 78 publications

References 180 publications

The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

The Potential Role of Nrf2-PD-L1 Axis in Promoting of Oxaliplatin Resistance in Colon Cancer Cells

PD‐1/PD‐L1‐dependent immune response in colorectal cancer

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

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