Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells

Fan, Hong; Paiboonrungruan, Chorlada; Zhang, Xinyan; Prigge, Justin R.; Schmidt, Edward E.; Sun, Zheng; Chen, Xiaoxin

doi:10.1016/j.bbrc.2017.08.049

Cited by 33 publications

(28 citation statements)

References 33 publications

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“…Recent literature suggests a cross talk between the NRF2 and Notch signaling pathways . We also showed that expression of both NICD1 and HES1 in oral squamous epithelial cells were regulated by NRF2, consistent with previous findings in hematopoietic stem cells, airway basal stem cells, and mouse embryonic fibroblasts . Although the Notch signaling pathway is believed to be anticarcinogenic through its regulation of squamous epithelial cell differentiation, several recent studies indicated that upregulation of the Notch signaling pathway may contribute to the malignant phenotype in these cells as well .…”

Section: How Does Nrf2 Hyperactivation Contribute To Escc?supporting

confidence: 91%

Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

Paiboonrungruan

Yan

et al. 2018

Annals of the New York Academy of Sciences

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Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research. Here, we review the current understanding of the functions of the nuclear factor erythroid-derived 2-like 2 (NRF2) signaling pathway in the esophagus. Genomic data suggest that gene mutations and several other mechanisms result in NRF2 hyperactivation in human ESCC. As a consequence, NRF2 ESCC is more resistant to chemoradiotherapy and associated with poorer survival than NRF2 ESCC. Mechanistically, we believe NRF2, functioning as a transcription factor, causes an esophageal phenotype through regulation of gene transcription. We discuss metabolism, mitochondria, proteasomes, and several signaling pathways as downstream players that may contribute to an esophageal phenotype due to NRF2 hyperactivation. Finally, strategies are proposed to target the NRF2 signaling pathway for therapy of NRF2 ESCC.

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Section: How Does Nrf2 Hyperactivation Contribute To Escc?supporting

confidence: 91%

Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

Paiboonrungruan

Yan

et al. 2018

Annals of the New York Academy of Sciences

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“…Initial studies mainly focused on the Warburg effect, while subsequent work also investigated changes in the one-carbon and fatty acids metabolism, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA) and glutamine catabolism [173,220,221]. In general, NRF2 can control multiple metabolic routes by two different mechanisms, similarly to other oncogenes (e.g., MYC or KRAS): the first involves direct transactivation of key metabolic enzymes [222], while the second relies on the modulation of proteins controlling other signaling pathways such as PPARγ [223], Notch [215,224], AHR [225,226] and PI3K/AKT [53]. It is known that alterations of tumor metabolism are often paralleled by an increased antioxidant capacity, which is also part of the adaptive response mounted by cancer cells to face adverse conditions, including OS [173,[227][228][229][230].…”

Section: Metabolic Reprogramming By Nrf2: Nadph Links Tumor Growth Anmentioning

confidence: 99%

Potential Applications of NRF2 Modulators in Cancer Therapy

et al. 2020

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The nuclear factor erythroid 2-related factor 2 (NRF2)–Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.

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“…Nrf2/HO-1 signaling activation promotes metastasis, angiogenesis, and chemotherapy and radiotherapy resistance of cancer cells [14,15]. Fan et al [23]. showed that Nrf2 overexpression increases proliferation, migration, and invasion of OSCC cells by regulating Notch signaling.…”

Section: Introductionmentioning

confidence: 99%

Oxysophocarpine Retards the Growth and Metastasis of Oral Squamous Cell Carcinoma by Targeting the Nrf2/HO-1 Axis

Liu

Jia

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oncogene in various types of cancers, including oral squamous cell carcinoma (OSCC). Oxysophocarpine (OSC) is a natural alkaloid that has multiple pharmacological activities. However, the biological functions and molecular mechanism underlying the effects of OSC on the growth and metastasis of OSCC are unclear. Methods: Nrf2 levels were determined in OSCC tissues and non-cancerous specimens by quantitative real-time PCR, western blotting, and immunohistochemistry (IHC) assays. The effects of OSC on OSCC cell growth and metastasis were explored (1) using 5-ethynyl-20-deoxyuridine staining and Cell Counting Kit-8, colony formation, flow cytometry, wound-healing, Transwell, and tube formation assays in vitro; and (2) by establishing a xenograft nude mouse model in vivo. The molecular mechanisms underlying the effects of OSC on the growth and metastasis of OSCC were investigated in vitro by western blotting, caspase-3 activity, and enzyme-linked immunosorbent assays, and in vivo by western blotting and IHC assays. Results: The expression levels of Nrf2 in OSCC tissues and in cell lines were much higher than in non-cancerous tissues and normal oral keratinocytes. The upregulation of Nrf2 was positively correlated with a high incidence of lymph node metastasis and advanced histological grade and TNM stage, but inversely associated with differentiation and survival of OSCC patients. OSC reduced the expression of Nrf2 and heme oxygenase 1 (HO-1) in OSCC cells. OSC also inhibited proliferation, migration, invasion, and pro-angiogenesis of OSCC cells. Moreover, OSC induced cell cycle arrest, enhanced apoptosis of OSCC cells in vitro, and decreased OSCC tumor growth in vivo. Mechanically, OSC reduced the aggressive behavior of OSCC cells by inactivation of the Nrf2/HO-1 signaling pathway. Conclusion: Our findings provide evidence that OSC inhibits the growth and metastasis of OSCC by targeting the Nrf2/ HO-1 axis, suggesting that OSC may be a potential therapeutic agent for OSCC.

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Nrf2 regulates cellular behaviors and Notch signaling in oral squamous cell carcinoma cells

Cited by 33 publications

References 33 publications

Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

Targeted therapy of esophageal squamous cell carcinoma: the NRF2 signaling pathway as target

Potential Applications of NRF2 Modulators in Cancer Therapy

Oxysophocarpine Retards the Growth and Metastasis of Oral Squamous Cell Carcinoma by Targeting the Nrf2/HO-1 Axis

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