The dual role of Nrf2 in melanoma: a systematic review

Abstract

Melanoma is the most lethal type of skin cancer that originates from the malignant transformation of melanocytes. Although novel treatments have improved patient survival in melanoma, the overall prognosis remains poor. To improve current therapies and patients outcome, it is necessary to identify the influential elements in the development and progression of melanoma.Due to UV exposure and melanin synthesis, the melanocytic lineage seems to have a higher rate of ROS (reactive oxygen species) formation. Melanoma has been linked to an increased oxidative state, and all facets of melanoma pathophysiology rely on redox biology. Several redox-modulating pathways have arisen to resist oxidative stress. One of which, the Nrf2 (nuclear factor erythroid 2-related factor 2), has been recognized as a master regulator of cellular response to oxidative or electrophilic challenges. The activation of Nrf2 signaling causes a wide range of antioxidant and detoxification enzyme genes to be expressed. As a result, this transcription factor has lately received a lot of interest as a possible cancer treatment target.On the other hand, Nrf2 has been found to have a variety of activities in addition to its antioxidant abilities, constant Nrf2 activation in malignant cells may accelerate metastasis and chemoresistance. Hence, based on the cell type and context, Nrf2 has different roles in either preventing or promoting cancer. In this study, we aimed to systematically review all the studies discussing the function of Nrf2 in melanoma and the factors determining its alteration.

Acyltransferase zinc finger DHHC-type containing 2 aggravates gastric carcinoma growth by targeting Nrf2 signaling: A mechanism-based multicombination bionic nano-drug therapy

“…Considering the complicated tumorigenesis and chemoresistance identified in progressive gastric cancer with metastasis, malignant ascites and tissue infiltration, a series of potential targeted drugs in clinical trials did not meet the expected requirements. Currently, Nrf2, a key transcription factor, exhibits a vital role in redox regulation challenge and control of the innate immune response and cell survival by promoting the antioxidant response [ 29 , 30 ]. However, as a “double-faced' role in tumorigenesis regulation, a series of compounds that target Nrf2 to regulate gene expression and then act as a chemical prevention, including synthetic chemicals (i.e., Oltipraz) and some natural active products, such as curcumin, sulforaphane, resvertrol have been identified [ 31 , 32 ].…”

Cellular Basis of Adjuvant Role of n-3 Polyunsaturated Fatty Acids in Cancer Therapy: Molecular Insights and Therapeutic Potential against Human Melanoma

“…Conversely, Nrf2 has been implicated in a spectrum of activities, and sustained activation of Nrf2 in malignant cells may expedite processes such as metastasis and chemoresistance. This duality suggests that Nrf2 may assume distinct roles, either acting to prevent or promote cancer, adding complexity to its potential therapeutic implications and consequently there has been a growing interest in exploring this transcription factor as a potential target for cancer treatment [160]. However, to date, there are no studies that account for this modulation by PUFAs and Nrf2 in melanoma.…”

Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma

“…When ROS/RNS are produced in excess with respect to the antioxidant defenses, oxidative stress occurs. One of the main proteins involved in regulating antioxidant response is the Nuclear factor E2-related factor 2 (Nrf2), a transcription factor that has been found to play a pivotal role in several types of cancer [ 14 ], including melanoma [ 15 , 16 ]. In physiological conditions, Nrf2 is located in the cytosol, where it is coupled to its inhibitor Kelch-like ECH-associated protein (KEAP1), resulting in its degradation via ubiquitination and proteasomal-dependent proteolysis.…”

“…Thus, Nrf2 is released, and it can translocate into the nucleus where it binds to the Antioxidant Response Elements (ARE) sequences located in the promoter of specific antioxidant and cytoprotective genes, including Heme oxygenase-1 (HO-1) and numerous genes related to glutathione (GSH) metabolism, such as γ-glutamate cysteine ligase and glutathione-S-transferase A4 (GSTA4) [ 14 ]. Nrf2 can be a double-edged sword in several types of cancers, including melanoma [ 16 , 17 ]. Indeed, a cytoprotective role for Nrf2 has been recognized in the early stages of malignant transformation due to its ability to inhibit tumor growth, detoxify carcinogens, and protect cells from oxidative stress damage.…”

“…However, an opposite role of Nrf2 in the advanced stages of the cancer disease has been highlighted since aberrant activations of Nrf2 are associated with poor prognosis, induction of pro-survival genes, promotion of cancer cell proliferation by metabolic reprogramming, and enhancement of the self-renewal capacity of cancer stem cells. Interestingly, Nrf2 is involved in resistance to chemotherapeutic drugs and radiation treatments [ 16 , 17 , 18 , 19 ]. In melanoma, immunohistochemistry studies revealed that Nrf2 protein expression correlated with deeper Breslow, invasive phenotype, nodular growth, and worse survival [ 20 ].…”