The Nrf2 transcription factor contributes to resistance to cisplatin in bladder cancer

Hayden, Annette; Douglas, James J.; Sommerlad, Matthew; Andrews, Lawrence P.; Gould, Katherine A.; Hussain, Syed A.; Thomas, Gareth J.; Packham, Graham; Crabb, Simon J.

doi:10.1016/j.urolonc.2014.02.006

Cited by 80 publications

(68 citation statements)

References 25 publications

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“…This resistance has been attributed to NRF2-induced GSH increase that conjugates cisplatin and facilitates extrusion outside cells. The increased NRF2 was closely associated with unfavorable overall and recurrence-free survival in patients who received cisplatin-based chemotherapy, however, NRF2 depletion restores their cisplatin sensitivity and prolongs the lifetime by about two years (Hayden et al, 2014).…”

Section: Other Cancersmentioning

confidence: 96%

“…Construction of lentiviral vector system that consists of gene (with ARE in its promoter) encoding for siRNA or shRNA improves their tumor-and NRF2-targeting property. In combination with other anticancer treatments, NRF2 knockdown turns out to be a more effective anticancer strategy by which resistance to a wide variety of chemotherapeutic drugs, including DOX (Shim et al, 2009), cisplatin , 5-FU (Hayden et al, 2014), PTX (Hu et al, 2010), gemcitabine (Lister et al, 2011), etoposide (Wang et al, 2008b) and bleomycin (Homma et al, 2009) can be reduced.…”

Section: Novel Nrf2 Targeted Strategiesmentioning

confidence: 99%

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Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Bai

Chen

Hou

et al. 2016

Drug Metabolism Reviews

134

105

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Chemoresistance is a disturbing barrier in cancer therapy, which always results in limited therapeutic options and unfavorable prognosis. Nuclear factor E2-related factor 2 (NRF2) controls the expression of genes encoding cytoprotective enzymes and transporters that protect against oxidative stress and electrophilic injury to maintain intrinsic redox homeostasis. However, recent studies have demonstrated that aberrant activation of NRF2 due to genetic and/or epigenetic mutations in tumor contributes to the high expression of phase I and phase II drug-metabolizing enzymes, phase III transporters, and other cytoprotective proteins, which leads to the decreased therapeutic efficacy of anticancer drugs through biotransformation or extrusion during chemotherapy. Therefore, a better understanding of the role of NRF2 in regulation of these enzymes and transporters in tumors is necessary to find new strategies that improve chemotherapeutic efficacy. In this review, we summarized the recent findings about the chemoresistance-promoting role of NRF2, NRF2-regulated phase I and phase II drug-metabolizing enzymes, phase III drug efflux transporters, and other cytoprotective genes. Most importantly, the potential of NRF2 was proposed to counteract drug resistance in cancer treatment.

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Section: Other Cancersmentioning

confidence: 96%

Section: Novel Nrf2 Targeted Strategiesmentioning

confidence: 99%

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Bai

Chen

Hou

et al. 2016

Drug Metabolism Reviews

134

105

View full text Add to dashboard Cite

show abstract

“…Increased NRF2 expression has been extensively studied in patients with head and neck cancer [42–44], lung cancer [45–50], gall bladder cancer [51, 52], epithelial ovarian cancer [53], osteosarcoma [54], breast cancer [55], bladder cancer [56], colorectal cancer [57], gastric cancer [58], glioblastoma [59, 60], and pancreatic cancer [61]. In these patients, Nrf2 expression is significantly correlated with increased proliferation and treatment resistance to radiation, cisplatin, and 5-fluorouracil (5-FU), seemingly through the induction of antioxidant genes [44, 45, 48, 53, 55, 58].…”

Section: Oncogenic Roles Of Nrf2mentioning

confidence: 99%

Dual roles of NRF2 in tumor prevention and progression: Possible implications in cancer treatment

Moon

Giaccia

2015

Free Radical Biology and Medicine

142

112

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The Cap’N’Collar (CNC) family serves as cellular sensors of oxidative and electrophilic stresses and shares structural similarities including basic leucine zipper (bZIP) and CNC domains,. They form heterodimers with small MAF proteins to regulate antioxidant and phase II enzymes through antioxidant response element (ARE)-mediated transactivation. Among the CNC family members, NRF2 is required for systemic protection against redox-mediated injury and carcinogenesis. On the other hand, NRF2 is activated by oncogenic pathways, metabolism, and hypoxia. Constitutive NRF2 activation is observed in a variety of human cancers and it is highly correlated with tumor progression and aggressiveness. In this review, we will discuss how NRF2 plays dual roles in cancer prevention and progression depending on the cellular context and environment. Therefore, a better understanding of NRF2 will be necessary to exploit this complex network of balancing antioxidant pathways to inhibit tumor progression.

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“…4E). Nrf2 exhibits a critical function in the induction of phase II detoxifying enzymes, including glutamate-L-cysteine ligase catalytic subunit, nicotinamide adenine dinucleotide (P) H: quinone oxidoreductase and heme oxygenase-1, via the Kelch-like ECH-associated protein 1-Nrf2-ARE pathway, which has been reported to induce CDDP resistance in tumor cells (51,52). Although Nrf2 and its target gene contribute to CDDP resistance, the present authors postulate that it is not advisable to increase CDDP cytotoxicity via Nrf2 suppression.…”

Section: Discussionmentioning

confidence: 99%

xCT expression modulates cisplatin resistance in Tca8113 tongue carcinoma cells

et al. 2016

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Abstract. Tongue squamous cell carcinoma (TSCC), which is a subtype of head and neck cancer, is the most common type of oral cancer. Due to its high recurrence rate and chemoresistance, the average survival rate for patients with TSCC remains unsatisfactory. At present, cisplatin (CDDP) is utilized as the first-line treatment for numerous solid neoplasms, including TSCC. CDDP resistance develops in the majority of patients; however, the mechanism of such resistance remains unknown. Therefore, the present study aimed to clarify the mechanism of CDDP resistance and attempted to reduce chemoresistance. The results indicated that CDDP significantly increased expression of xCT, which is the light chain and functional subunit of the glutamate/cysteine transporter system x c -, and a subsequent increase in glutathione (GSH) levels was observed. The present study demonstrated that the upregulation of xCT expression and intercellular GSH levels contributed to CDDP resistance in TSCC cells. Furthermore, xCT suppression, induced by small interfering RNA or pharmacological inhibitors, sensitized TSCC cells to CDDP treatment. In conclusion, the present study revealed that CDDP-induced xCT expression promotes CDDP chemoresistance, and xCT inhibition sensitizes TSCC cells to CDDP treatment. These results provide a novel insight into the molecular mechanisms involved in TSCC cell chemoresistance.

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The Nrf2 transcription factor contributes to resistance to cisplatin in bladder cancer

Cited by 80 publications

References 25 publications

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Dual roles of NRF2 in tumor prevention and progression: Possible implications in cancer treatment

xCT expression modulates cisplatin resistance in Tca8113 tongue carcinoma cells

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