The molecular biology and therapeutic potential of Nrf2 in leukemia

Abstract

NF-E2-related factor 2 (Nrf2) transcription factor has contradictory roles in cancer, which can act as a tumor suppressor or a proto-oncogene in different cell conditions (depending on the cell type and the conditions of the cell environment). Nrf2 pathway regulates several cellular processes, including signaling, energy metabolism, autophagy, inflammation, redox homeostasis, and antioxidant regulation. As a result, it plays a crucial role in cell survival. Conversely, Nrf2 protects cancerous cells from apoptosis and increases proliferation, angiogenesis, and metastasis. It promotes resistance to chemotherapy and radiotherapy in various solid tumors and hematological malignancies, so we want to elucidate the role of Nrf2 in cancer and the positive point of its targeting. Also, in the past few years, many studies have shown that Nrf2 protects cancer cells, especially leukemic cells, from the effects of chemotherapeutic drugs. The present paper summarizes these studies to scrutinize whether targeting Nrf2 combined with chemotherapy would be a therapeutic approach for leukemia treatment. Also, we discussed how Nrf2 and NF-κB work together to control the cellular redox pathway. The role of these two factors in inflammation (antagonistic) and leukemia (synergistic) is also summarized.

Antitumor Effect of Brusatol in Acute Lymphoblastic Leukemia Models Is Triggered by Reactive Oxygen Species Accumulation

“…Oxidative stress (OS) is involved in cancer development, namely in leukemogenesis and therapy resistance [ 6 , 7 ]. Nuclear factor erythroid 2-related factor-2 (NRF2) is a key transcription factor that regulates multiple pathways, for instance, glutathione synthesis, reactive oxygen species (ROS) scavenging, drug excretion and detoxification, and NADP synthesis [ 8 ].…”

“…Nuclear factor erythroid 2-related factor-2 (NRF2) is a key transcription factor that regulates multiple pathways, for instance, glutathione synthesis, reactive oxygen species (ROS) scavenging, drug excretion and detoxification, and NADP synthesis [ 8 ]. It is the main regulator of antioxidant responses and ROS levels, tightly controlled and regulated by its natural inhibitor, the kelch-like ECH-associated protein 1 (KEAP1) [ 7 ].…”

Targeting Nrf2 signaling pathway by quercetin in the prevention and treatment of neurological disorders: An overview and update on new developments

“…The Nrf2/MAF heterodimer functions as a transcription factor that attaches to the ARE zone of the chromosomal promoter and stimulates the translation of a variety of genes, particularly genes involved in cytoprotection and detoxification. Reduced ROS production and cell equilibrium are maintained by translated genes [79][80][81]. ROS alters KEAP1's structurally during OS, preventing it from binding to Nrf2.…”

Nrf2 Regulates Oxidative Stress and Its Role in Cerebral Ischemic Stroke

“…It is a transcription factor with a highly conserved basic leucine zipper structure, and is regulated by Keap1 at a low level and has a short half-life in non-activated cells [ 34 ]. Nrf2 mainly has seven highly conserved epichlorohydrin-related protein homologous domains (Nrf2 epichlorohydrin homology, Neh) [ 10 , 35 ] ( Figure 1 ): The Neh1 region is a leucine zipper motif associated with intranuclear small musculoaponeurotic fibrosarcoma (sMaf), forms a heterodimer, recognizes and binds related sequences on the ARE, and can also interact with E2 ubiquitin-binding enzyme to adjust Nrf2 stability. The Neh2 region is a Keap1-dependent regulatory region, which contains two binding units, DLG and ETGE, to negatively regulate the Nrf2 transcriptional activity and promote its degradation [ 36 ].…”

“…The cytoplasmic kelch-like epichlorohydrin-associated protein 1 (Keap1) can sense the oxidative insults, and Nrf2 will serve for the counter responses [ 9 ]. More than 600 genes, among them more than 200 encoding proteins linked to inflammation, cancer, neurological disorders, aging, cardiovascular disease, and other serious illnesses, are regulated by the Nrf2 signaling pathway [ 10 ]. Nrf2 can regulate most downstream factors, and it can play plenty of roles, including antiapoptosis, anti-inflammatory injury, reducing calcium overload, antioxidative stress, etc., and help the body maintain the redox reaction of brain tissue and brain cells.…”