NRF2 and the Hallmarks of Cancer

Vega, Montserrat Rojo de la; Chapman, Eli; Zhang, Donna D.

doi:10.1016/j.ccell.2018.03.022

Cited by 1,210 publications

(924 citation statements)

References 335 publications

(479 reference statements)

Supporting

Mentioning

906

Contrasting

Unclassified

Order By: Relevance

“…It is a "Master redox switch" as it is known to control the basal and inducible expression of hundreds of cytoprotective genes containing antioxidant response elements (AREs) in their regulatory regions by heterodimerizing with small musculoaponeurotic fibrosarcoma (MAF) proteins . NRF2 target genes control redox homeostasis, drug metabolism and elimination, energetic, iron and amino acid metabolisms, cell survival, proliferation, autophagy, proteasomal degradation, DNA repair, and mitochondrial physiology . Under basal conditions, NRF2 is held in the cytoplasm as an inactive complex bound to the repressor molecule KEAP1, which is also an adaptor protein of E3 ubiquitin ligase which in turn facilitates NRF2 ubiquitination (Figure ).…”

Section: Main Cellular Targets Relevant To Its Clinical (Anti‐inflammmentioning

confidence: 99%

Dimethyl fumarate, a two‐edged drug: Current status and future directions

Saidu

Kavian

Leroy

et al. 2019

Medicinal Research Reviews

120

100

View full text Add to dashboard Cite

Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing‐remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine‐rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF‐E2)–related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose‐dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2. Some other studies performed indicate also the potential role of DMF in cancers, which are dependent on the NRF2 antioxidant and cellular detoxification program, such as KRAS‐mutated lung adenocarcinoma. It, however, seems that DMF has multiple biological effects as it has been shown to also inhibit the transcription factor nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), thus blocking downstream targets that may be involved in the development and progression of inflammatory cascades leading to various disease processes, including tumors, lymphomas, diabetic retinopathy, arthritis, and psoriasis. Herein, we present the current status and future directions of the use of DMF in various diseases models with particular emphases on its targeting of specific intracellular signal transduction cascades in cancer; to shed some light on its possible mode of action.

show abstract

Section: Main Cellular Targets Relevant To Its Clinical (Anti‐inflammmentioning

confidence: 99%

Dimethyl fumarate, a two‐edged drug: Current status and future directions

Saidu

Kavian

Leroy

et al. 2019

Medicinal Research Reviews

120

100

View full text Add to dashboard Cite

show abstract

“…5 In recent years, accumulating evidence implies the importance of Nrf2 deregulation in tumourigenesis. 6 Under physiological conditions, Nrf2 localizes in the cytoplasm where it is bound by Kelch-like ECH-associated protein 1 (Keap1). Several types of cancer cells display a large amount of reactive oxygen species (ROS), due to an aberrant metabolism, mitochondrial dysfunction or activation of oncogenes.…”

mentioning

confidence: 99%

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

Zhang

et al. 2019

J Cellular Molecular Medi

150

100

View full text Add to dashboard Cite

Abnormal metabolism of tumour cells is closely related to the occurrence and development of breast cancer, during which the expression of NF‐E2‐related factor 2 (Nrf2) is of great significance. Metastatic breast cancer is one of the most common causes of cancer death worldwide; however, the molecular mechanism underlying breast cancer metastasis remains unknown. In this study, we found that the overexpression of Nrf2 promoted proliferation and migration of breast cancers cells. Inhibition of Nrf2 and overexpression of Kelch‐like ECH‐associated protein 1 (Keap1) reduced the expression of glucose‐6‐phosphate dehydrogenase (G6PD) and transketolase of pentose phosphate pathway, and overexpression of Nrf2 and knockdown of Keap1 had opposite effects. Our results further showed that the overexpression of Nrf2 promoted the expression of G6PD and Hypoxia‐inducing factor 1α (HIF‐1α) in MCF‐7 and MDA‐MB‐231 cells. Overexpression of Nrf2 up‐regulated the expression of Notch1 via G6PD/HIF‐1α pathway. Notch signalling pathway affected the proliferation of breast cancer by affecting its downstream gene HES‐1, and regulated the migration of breast cancer cells by affecting the expression of EMT pathway. The results suggest that Nrf2 is a potential molecular target for the treatment of breast cancer and targeting Notch1 signalling pathway may provide a promising strategy for the treatment of Nrf2‐driven breast cancer metastasis.

show abstract

“…p62 is known as a multifunctional signaling hub, as it participates in the activation of mTORC1 (mechanistic target of rapamycin complex 1) in nutrient sensing [15], NF-jB activation during inflammation and apoptosis [23] and the activation of the Keap1-Nrf2 pathway for antioxidant response [24], as well as its mentioned receptor role in selective autophagy [25]. Alterations in all these pathways have been associated with cancer development [26][27][28][29]. Here, we describe how the interplay between p62 and the Nrf2, mTORC1, NF-jB, and autophagy pathways plays a key cellular role both in homeostatic conditions and during cancer development.…”

mentioning

confidence: 99%

p62/SQSTM1: ‘Jack of all trades’ in health and cancer

2018

View full text Add to dashboard Cite

p62 is a stress‐inducible protein able to change among binding partners, cellular localizations and form liquid droplet structures in a context‐dependent manner. This protein is mainly defined as a cargo receptor for selective autophagy, a process that allows the degradation of detrimental and unnecessary components through the lysosome. Besides this role, its ability to interact with multiple binding partners allows p62 to act as a main regulator of the activation of the Nrf2, mTORC1, and NF‐κB signaling pathways, linking p62 to the oxidative defense system, nutrient sensing, and inflammation, respectively. In the present review, we will present the molecular mechanisms behind the control p62 exerts over these pathways, their interconnection and how their deregulation contributes to cancer progression.

show abstract

NRF2 and the Hallmarks of Cancer

Cited by 1,210 publications

References 335 publications

Dimethyl fumarate, a two‐edged drug: Current status and future directions

Dimethyl fumarate, a two‐edged drug: Current status and future directions

Nrf2 promotes breast cancer cell migration via up‐regulation of G6PD/HIF‐1α/Notch1 axis

p62/SQSTM1: ‘Jack of all trades’ in health and cancer

Contact Info

Product

Resources

About