Nrf2 signaling pathway: current status and potential therapeutic targetable role in human cancers

Abstract

Cancer is a borderless global health challenge that continues to threaten human health. Studies have found that oxidative stress (OS) is often associated with the etiology of many diseases, especially the aging process and cancer. Involved in the OS reaction as a key transcription factor, Nrf2 is a pivotal regulator of cellular redox state and detoxification. Nrf2 can prevent oxidative damage by regulating gene expression with antioxidant response elements (ARE) to promote the antioxidant response process. OS is generated with an imbalance in the redox state and promotes the accumulation of mutations and genome instability, thus associated with the establishment and development of different cancers. Nrf2 activation regulates a plethora of processes inducing cellular proliferation, differentiation and death, and is strongly associated with OS-mediated cancer. What’s more, Nrf2 activation is also involved in anti-inflammatory effects and metabolic disorders, neurodegenerative diseases, and multidrug resistance. Nrf2 is highly expressed in multiple human body parts of digestive system, respiratory system, reproductive system and nervous system. In oncology research, Nrf2 has emerged as a promising therapeutic target. Therefore, certain natural compounds and drugs can exert anti-cancer effects through the Nrf2 signaling pathway, and blocking the Nrf2 signaling pathway can reduce some types of tumor recurrence rates and increase sensitivity to chemotherapy. However, Nrf2’s dual role and controversial impact in cancer are inevitable consideration factors when treating Nrf2 as a therapeutic target. In this review, we summarized the current state of biological characteristics of Nrf2 and its dual role and development mechanism in different tumor cells, discussed Keap1/Nrf2/ARE signaling pathway and its downstream genes, elaborated the expression of related signaling pathways such as AMPK/mTOR and NF-κB. Besides, the main mechanism of Nrf2 as a cancer therapeutic target and the therapeutic strategies using Nrf2 inhibitors or activators, as well as the possible positive and negative effects of Nrf2 activation were also reviewed. It can be concluded that Nrf2 is related to OS and serves as an important factor in cancer formation and development, thus provides a basis for targeted therapy in human cancers.

Interplay of oxidative stress, cellular communication and signaling pathways in cancer

“…The Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathway is also susceptible to modulation by ROS [ 37 ]. Oxidative stress can induce the activation of JAKs, which in turn phosphorylate and activate STATs; activated STATs translocate to the nucleus and regulate the expression of genes involved in inflammation, cell proliferation, and apoptosis [ 37 , 38 ].…”

Contribution of Immune Responses to the Cardiotoxicity and Hepatotoxicity of Deltamethrin in Early Life Stage Zebrafish (Danio rerio)

“…Changes in tissue morphology have been previously shown to be associated with oxidative stress. − Overproduction of ROS, reactive nitrogen species, and nitric oxide, can alter antioxidant status and lead to lipid, DNA, and protein oxidative damage, resulting in apoptosis and autophagy . Increased ROS levels following exposure to DM and other pyrethroids have been well demonstrated in vivo and in vitro. ,, However, it remains unclear at which step ROS generation or oxidative stress occurs during DM exposure .…”

Investigation of Epilobium hirsutum L. Optimized Extract’s Anti-Inflammatory and Antitumor Potential

“…NRF2 is involved in the inflammation process by recruiting inflammatory cells as well as regulating the expression of pro-inflammatory genes, such as COX2 and iNOS [ 74 ]. When activated, NRF2 translocates to the nucleus and binds to Antioxidant Response Elements (ARE) in the promoter regions of various genes involved in antioxidant and cytoprotective responses [ 75 , 76 ]. This activation leads to the upregulation of several antioxidative enzymes and proteins, thereby enhancing the cell’s capacity to neutralize reactive oxygen species (ROS) and protect against oxidative damage [ 76 , 77 ].…”

“…When activated, NRF2 translocates to the nucleus and binds to Antioxidant Response Elements (ARE) in the promoter regions of various genes involved in antioxidant and cytoprotective responses [ 75 , 76 ]. This activation leads to the upregulation of several antioxidative enzymes and proteins, thereby enhancing the cell’s capacity to neutralize reactive oxygen species (ROS) and protect against oxidative damage [ 76 , 77 ]. The induction of NRF2 in our study suggests an enhanced cellular response to mitigate oxidative stress, which is a critical factor in the context of inflammation.…”