The Role of Nrf2 Activity in Cancer Development and Progression

Abstract

Nrf2 is a transcription factor that stimulates the expression of genes which have antioxidant response element-like sequences in their promoter. Nrf2 is a cellular protector, and this principle applies to both normal cells and malignant cells. While healthy cells are protected from DNA damage induced by reactive oxygen species, malignant cells are defended against chemo- or radiotherapy. Through our literature search, we found that Nrf2 activates several oncogenes unrelated to the antioxidant activity, such as Matrix metallopeptidase 9 (MMP-9), B-cell lymphoma 2 (BCL-2), B-cell lymphoma-extra large (BCL-xL), Tumour Necrosis Factor α (TNF-α), and Vascular endothelial growth factor A (VEGF-A). We also did a brief analysis of The Cancer Genome Atlas (TCGA) data of lung adenocarcinoma concerning the effects of radiation therapy and found that the therapy-induced Nrf2 activation is not universal. For instance, in the case of recurrent disease and radiotherapy, we observed that, for the majority of Nrf2-targeted genes, there is no change in expression level. This proves that the universal, axiomatic rationale that Nrf2 is activated as a response to chemo- and radiation therapy is wrong, and that each scenario should be carefully evaluated with the help of Nrf2-targeted genes. Moreover, there were nine genes involved in lipid peroxidation, which showed underexpression in the case of new radiation therapy: ADH1A, ALDH3A1, ALDH3A2, ADH1B, GPX2, ADH1C, ALDH6A1, AKR1C3, and NQO1. This may relate to the fact that, while some studies reported the co-activation of Nrf2 and other oncogenic signaling pathways such as Phosphoinositide 3-kinases (PI3K), mitogen-activated protein kinase (MAPK), and Notch1, other reported the inverse correlation between Nrf2 and the tumor-promoter Transcription Factor (TF), Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Lastly, Nrf2 establishes its activity through interactions at multiple levels with various microRNAs. MiR-155, miR-144, miR-28, miR-365-1, miR-93, miR-153, miR-27a, miR-142, miR-29-b1, miR-340, and miR-34a, either through direct repression of Nrf2 messenger RNA (mRNA) in a Kelch-like ECH-associated protein 1 (Keap1)-independent manner or by enhancing the Keap1 cellular level, inhibit the Nrf2 activity. Keap1–Nrf2 interaction leads to the repression of miR-181c, which is involved in the Nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling pathway. Nrf2’s role in cancer prevention, diagnosis, prognosis, and therapy is still in its infancy, and the future strategic planning of Nrf2-based oncological approaches should also consider the complex interaction between Nrf2 and its various activators and inhibitors.

Activation of NRF2 by topical apocarotenoid treatment mitigates radiation-induced dermatitis

“…Interestingly, studies have shown that systemic upregulation of NRF2 can be radioprotective [ 60 ], while our own previous work has indicated that bixin can upregulate NRF2 systemically causing skin photoprotection [ 28 , 61 ]. However, in the context of this study, topical bixin administration seems preferable as it could limit NRF2 induction to the skin, thus minimizing NRF2 modulation throughout the body, and ultimately maintaining the desired sensitivity of specific tissues to radiotherapy [ [62] , [63] , [64] ]. While IR effects on cultured and epidermal keratinocytes are the primary focus of these experiments, the role of inflammatory factors including immune cell infiltration and response, all of which might be subject to modulation by NRF2, deserves further studies as it was not addressed in this prototype investigation.…”

Glucose starvation to rapid death of Nrf1, but not Nrf2, deficient hepatoma cells from its fatal defects in the redox metabolism reprogramming

“…Such surprising result implies that Nrf2 may also contribute to ROS production in Nrf1α / cells under basal and glucose deprivation conditions, albeit it has been accepted as a master regulator of antioxidant cytoprotective genes [44]. This is also supported by the finding that Nrf1α / cells are maintained at higher ROS levels in almost unstressed conditions, while Nrf2 −/− cells are preserved at relatively lower ROS levels than those of wild-type Nrf1/2 +/+ cells (in this study).…”

Targeting the Redox Landscape in Cancer Therapy

“…Furthermore, basal Nrf2 levels can increase during chemo-or radiotherapy, which correlates with therapy resistance [173]. On the other hand, Nrf2 plays a protective role and prevents cancer development by reducing ROS levels [172,173]. This implies a dual role for Nrf2 in cancer development and suggests that optimal therapy likely depend on cancer stage or cancer type, as summarized in Milkovic et al [176].…”

“…The exact role of Nrf2 in carcinogenesis remains unclear. On the one hand, it has been shown that Nrf2 is upregulated in various cancers [172,173], which is caused either by DNA methylation in the promoter region of Keap1, constitutive Nrf2 activation, or mutations in the Keap1 domain [174,175]. Furthermore, basal Nrf2 levels can increase during chemo-or radiotherapy, which correlates with therapy resistance [173].…”