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Role of NRF2 in Lung Cancer

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Role of NRF2 in Lung Cancer cells Review Role of NRF2 in Lung Cancer Miriam Sánchez-Ortega, Ana Clara Carrera and Antonio Garrido * Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid, Cantoblanco, E-28049 Madrid, Spain; [email protected] (M.S.-O.); [email protected] (A.C.C.) * Correspondence: [email protected] Abstract: The gene expression program induced by NRF2 transcription factor plays a critical role in cell defense responses against a broad variety of cellular stresses, most importantly oxidative stress. NRF2 stability is fine-tuned regulated by KEAP1, which drives its degradation in the absence of oxidative stress. In the context of cancer, NRF2 cytoprotective functions were initially linked to anti-oncogenic properties. However, in the last few decades, growing evidence indicates that NRF2 acts as a tumor driver, inducing metastasis and resistance to chemotherapy. Constitutive activation of NRF2 has been found to be frequent in several tumors, including some lung cancer sub-types and it has been associated to the maintenance of a malignant cell phenotype. This apparently contradictory effect of the NRF2/KEAP1 signaling pathway in cancer (cell protection against cancer versus pro- tumoral properties) has generated a great controversy about its functions in this disease. In this review, we will describe the molecular mechanism regulating this signaling pathway in physiological conditions and summarize the most important findings related to the role of NRF2/KEAP1 in lung cancer. The focus will be placed on NRF2 activation mechanisms, the implication of those in lung cancer progression and current therapeutic strategies directed at blocking NRF2 action. Keywords: NRF2 activation; NSCLC; therapeutic strategies Citation: Sánchez-Ortega, M.; Carrera, A.C.; Garrido, A. Role of NRF2 in Lung Cancer. Cells 2021, 10, 1. Introduction 1879. https://doi.org/ 10.3390/ Lung cancer, one of the most commonly diagnosed malignancies, has some of the cells10081879 lowest 5-year survival rates and is responsible for around 20% of all cancer-related deaths worldwide [1,2]. Histologically, this malignancy is classified into two groups: small- Academic Editor: Steven G. Gray cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) (the latter being the most frequent, around 85%). In small-cell lung cancer, the tumor derives from cells Received: 18 June 2021 of the neuroendocrine lineage upon loss of RB and TP53, whereas in non-small sub- Accepted: 21 July 2021 Published: 24 July 2021 types, the tumor originates from lung epithelia after distinct genetic events. NSCLC is further divided into three sub-types based mainly on the morphology of the transformed Publisher’s Note: MDPI stays neutral cells: adenocarcinoma (LUAD), squamous-cell carcinoma (LUSC) and large-cell carcinoma with regard to jurisdictional claims in (LCC) [3]. The observation that LUAD typically arises in the distal lung, whereas LUSC published maps and institutional affil- arises centrally, probably reflects different cells-of-origin for these two lung cancer sub- iations. types [4]. It is widely accepted that LUAD develops from alveolar type II (AT2) epithelial cells or cells within bronchioalveolar duct junctions, whereas LUSC develops from basal epithelial cells in airways [5]. LUSC differentiates into a stratified squamous epithelium that is not found in non-keratinizing epithelia. The third NSCLC sub-type, LCC, also originates from lung epithelial cells and represents a heterogeneous group of malignant Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. neoplasms that lack the cytological and architectural characteristics of small cell and This article is an open access article glandular carcinoma (LUAD) or squamous (LUSC) sub-types. All forms of lung cancer distributed under the terms and have poor prognosis, particularly SCLC and LUSC, which are typically observed in tobacco conditions of the Creative Commons smokers [6]. LCC has a relatively better prognosis (depends on sub-type). While LUAD Attribution (CC BY) license (https:// already has several available targeted therapies, SCLC has some therapies currently under creativecommons.org/licenses/by/ study [7]. In the case of LUSC, there is an urgent need for development of targeted therapies 4.0/). (Figure1). Cells 2021, 10, 1879. https://doi.org/10.3390/cells10081879 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 29 Cells 2021, 10, 1879 2 of 28 currently under study [7]. In the case of LUSC, there is an urgent need for development of targeted therapies (Figure 1). FigureFigure 1. Classification 1. Classification of lung of cancer. lung cancer. Lung Lungtumors tumors are divided are divided into two into main two groups: main groups: Small- Small-cellcell Lung CancerLung Cancer (SCLC; (SCLC; ≈15% ≈of15% cases) of cases)and Non and-small Non-small cell Lung cell LungCancer Cancer (NSCLC; (NSCLC; ≈85% ≈of85% cases). of cases). An An SCLC SCLCtumor tumorderives derives from neuroendocrine from neuroendocrine cell linage. cell linage.However, However, in NSCLC, in NSCLC, the tumor the origin tumor cell origin is cell different,is different, being classified being classified into three into different three different sub-types: sub-types: Adenocarcinoma Adenocarcinoma (LUAD; (LUAD;alveolar alveolartype II type epithelial cell), Squamous-cell Carcinoma (LUSC; basal epithelial cell) and Large-cell Carcinoma II epithelial cell), Squamous-cell Carcinoma (LUSC; basal epithelial cell) and Large-cell Carcinoma (LCC; various epithelial cells). (LCC; various epithelial cells). DuringDuring the past the half past-century, half-century, differen differentt bioinformatic bioinformatic and andnext next-generation-generation sequenc- sequencing ing analysanalyseses of of data data from from large large patient patient cohorts cohorts have have permitted the identificationidentification ofof keykeygenes genesinvolved involved inin the the generation generation and and progression progression of of many many tumor tumor types types [8, 9[8,9].]. In In this this context, context,the the Cancer Cancer Genome Genome Atlas Atlas (TCGA) (TCGA) consortium consortium and and other other projects projects have have found found thatthat some some genesgenes related to antioxidant antioxidant regulatory regulatory mechanisms, mechanisms, including including the the genes genes encoding encoding for for NRF2,NRF2, NFE2L2NFE2L2 (nuclear(nuclear factor factor erythroid erythroid 2-related 2-related factor factor 2) and 2) its and negative its negative regulator, regulator, KEAP1KEAP1 (Kelch(Kelch-like-like ECH- ECH-associatedassociated Protein Protein 1), are 1), altered are altered in several in several lung lung cancers cancers [10 [–1012]–12. ]. In In particular,particular, gain gain-of-function-of-function (GOF) (GOF) mutationsmutations of ofNFE2L2 NFE2L2or loss-of-functionor loss-of-function (LOF) (LOF) mutations mutationsof KEAP1 of KEAP1are frequent are frequent in NSCLC in NSCLC tumors tumors [13]. Indeed,[13]. Indeed,KEAP1 KEAP1mutations mutations are frequently are frequentlyfound found in LUAD in LUAD (17%) (17%) and LUSC and LUSC (12%), (12%), whereas whereasNFE2L2 NFE2L2mutations mutations are more are commonmore in commonLUSC in LUSC (15%) compared(15%) compared to LUAD to LUAD (3%) [10 (3%)]. Moreover, [10]. Moreover, 26% of 26% NSCLC of NSCLC tumors tumors present high presentexpression high expression of nuclear of NRF2nuclear [14 NRF2], with [14], a higher with incidence a higher inincidence the LUSC in sub-type the LUSC [10 ]. In sub-typeLCC, [10]. this In mutational LCC, thisphenomenon mutational phenomenon in NFE2L2/KEAP1 in NFE2L2/KEAP1is less common is [less15– 17common]. [15–17]. Based on initial studies, NRF2 was first considered a tumor suppressor gene, since Baseda number on initial of studies studies in, NRF2 other was cancer first types considered (i.e., colon, a tumor melanoma) suppressor and gene, in mice since showed a numberthat ofNFE2L2 studies deficiencyin other cancer increases types the(i.e. susceptibility, colon, melanoma) to cancer and [ 18in –mice20]. Moreshowed recently, that the NFE2L2linkage deficiency of GOF increases alterations the insusceptibilityNFE2L2 with to cancer cancer progression [18–20]. More and recently, an inefficient the link- response age ofto GOF classical alterations cancer in treatments NFE2L2 with (radiotherapy cancer progression and chemotherapy) and an inefficient in tumors response with to active classicalNRF2 cancer [21– treatments23] support (radiotherapy that NRF2 might and chemotherapy) act as a tumor driver in tum inors several with active cancer NRF2 sub-types [21–23](particularly support that in NRF2 LUAD might and LUSC). act as a This tumor dual driver role ofin NRF2 several as cancer tumor sub suppressor-types (par- or driver, ticularlydepending in LUAD on and the tumorLUSC). type This or dual stage, role has of given NRF2 rise as to tumor a substantial suppressor debate or aboutdriver, its role dependingin cancer on the [13 tumor]. type or stage, has given rise to a substantial debate about its role in cancer [13].In this review, we will describe how this signaling pathway works in physiological Inconditions this review and, we summarize will describe the most how important this signaling findings pathway related works to the in role physiological of NRF2/KEAP1 conditionsin LUAD and and summarize LUSC, focusing the onmost their important activation
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