The role of Nrf2-Keap1 axis in colorectal cancer, progression, and chemoresistance

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

doi:10.1177/1010428317705510

Cited by 53 publications

(36 citation statements)

References 115 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nrf2 overexpression has been reported in diverse types of tumors, associated with disease-free and shorter overall survival [4][5][6]. Furthermore, abnormal activation of Nrf2 signaling pathway has been demonstrated in CRC [7,8]. Kelch-like ECH−associated protein 1 (Keap1) is an adaptor protein, involving in ubiquitination and degradation of Nrf2, and directly regulating Nrf2 expression [9].…”

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, the constitutive activation of NRF2 common to metastatic cancer cells will result in many major modifications including altering the mitochondrial and cytosolic metabolism critical for tumor survival and metastasis [7] . NRF2 activation prevents cancer initiation [47,48] but in tumor cells promotes cancer progression as invasion, migration [49][50][51] and metastasis [52][53][54] , and also induces multidrug resistance to chemotherapy by upregulating expression of the multidrug resistance proteins (MDR)/P-glycoprotein/ABC drug transporters [55,56] . In this regard, NRF2 functions in a similar manner during ischemia-reperfusion of normal tissues in the body [57] as well as in the metabolic shift that occurs during induced pluripotent stem cell colony formation with reprogramming after an initial burst of OxPhos and increased ROS production which increases NRF2 before a temporal peak in HIF-1 mediated glycolysis and shuttling via the pentose phosphate pathway [58] .…”

Section: Constitutive Nrf2 Mediated Hif Activation and Reprogrammed Smentioning

confidence: 99%

NSAID celecoxib: a potent mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy

Ralph¹,

Nozuhur²,

Moreno‐Sánchez³

et al. 2018

JCMT

View full text Add to dashboard Cite

Intermittent hypoxia within tumor microenvironments causes pro-oxidative stress impairing oxidative phosphorylation (OxPhos) and increases mitochondrial production of reactive oxygen species (ROS). In primary tumors this provokes metabolic reprogramming of both tumor cells and cancer stem cells and emergence of highly metastatic cancer cells. Tumor reprogramming is initiated by activating nuclear respiratory factors and hypoxiainducible factors in response to changes in oxygen and ROS levels. Hence, hypoxia-induced pro-oxidative stress drives invasion and metastasis. However, it is also the Achilles' heel of metastatic cancer cells because pro-oxidative agents further overload the mitochondria and intracellular milieu with excessive ROS to trigger apoptosis, whereas antioxidant agents promote their survival and tumor progression. Herein lies the metastatic tumor cell sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) and we and others have shown that the NSAID celecoxib exerts powerful pro-oxidative anticancer effects by directly targeting mitochondria to increase ROS production and trigger cancer cell death, including metastatic cancer cells and cancer stem cells. This review highlights the considerable benefits from appropriate NSAID use in humans against post-diagnosis metastatic tumors and the need to further develop their use as adjuvant therapy for advanced stage metastatic disease where they are already showing significantly improved clinical outcomes.

show abstract

“…HO‐1 expression is highly increased in response to various stimuli like heme, nitric oxide, growth factor, cytokines, lipids . Nuclear factor erythroid 2‐related factor (Nrf2) is an important eukaryotic redoxactive factor and plays key roles in cytoprotection through regulating the expression of genes involved in anti‐oxidant, anti‐inflammatory, and detoxifying in mammals . Under unstressed conditions, transcriptional activity of Nrf2 can be suppressed by the interaction with kelch‐like ECH‐associated protein 1 (Keap1) .…”

Section: Introductionmentioning

confidence: 99%

“…14,15 Under unstressed conditions, transcriptional activity of Nrf2 can be suppressed by the interaction with kelch-like ECH-associated protein 1 (Keap1). 15,16 Exposure to oxidative stresses results in the dissociation of Keap1 from Nrf2, therefore Nrf2 translocate to the nucleus and binds to the ARE sequence of several cytoprotective genes to induce transcription, including HO-1 gene. 17 BTB and CNC homology 1 (Bach1) is a transcriptional repressor of HO-1, 18,19 and the antioxidant effect of HO-1 is enhanced in Bach1 deficiency mice.…”

mentioning

confidence: 99%

Protective effects of HO‐1 pathway on lung injury subsequent to limb ischemia reperfusion

Liu

et al. 2019

The Kaohsiung J of Med Scie

View full text Add to dashboard Cite

Limb ischemia reperfusion (LIR) can activate endogenous cytoprotective mechanisms by generating specific proteins against reperfusion injury in remote organs. The present study investigated the roles of heme oxygenase‐1 (HO‐1) pathway and the molecular mechanisms underlying the regulation of this pathway on lung injury following LIR. LIR was induced by ischemia for 4 hours followed by reperfusion for 6 hours (LIR 6 hours) or 16 hours (LIR 16 hours) in male Sprague‐Dawley rats. HO‐1 inducer cobalt protoporphyrin (Copp) or HO‐1 inhibitor zinc protoporphyrin (Znpp) was intravenously injected 24 hours before ischemia. The animals were randomly divided into nine groups, including normal control, LIR 6 hours, LIR 16 hours, Copp, Copp + LIR 6 hours, Copp + LIR 16 hours, and Znpp, Znpp+ LIR 6 hours, and Znpp + LIR 16 hours groups (each group included four samples). Lung injury was examined through histopathology. Quantitative real‐time PCR, immunohistochemistry and Western blot were applied to detect the mRNA and protein levels of HO‐1, Nrf2, and Bach1. Our study showed that LIR induced Nrf2 upregulation but Bach1 downregulation to promote HO‐1 expression in lung tissues. Activation of HO‐1 pathway by Copp potentially enhanced Nrf2 expression but inhibition of the pathway by Znpp promoted Bach1 expression. Inducer of HO‐1 pathway, Copp injection improved the lung injury. Nevertheless, Znpp injection aggravated the lung injury following LIR. Our findings suggested that activated HO‐1 pathway might exert protective effects on the lung injury following LIR.

show abstract

The role of Nrf2-Keap1 axis in colorectal cancer, progression, and chemoresistance

Cited by 53 publications

References 115 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

NSAID celecoxib: a potent mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy

Protective effects of HO‐1 pathway on lung injury subsequent to limb ischemia reperfusion

Contact Info

Product

Resources

About