Molecule Information

General Information of the Molecule (ID: Mol00126)

• Name: NFE2-related factor 2 (NRF2) ,Homo sapiens
• Synonyms: NF-E2-related factor 2; NFE2-related factor 2; Nrf-2; HEBP1; Nuclear factor; erythroid derived 2; like 2; NRF2
• Molecule Type: Protein
• Gene Name: NFE2L2
• Gene ID: 4780
• Location: chr2:177227595-177392697[-]
• Sequence:
  MMDLELPPPGLPSQQDMDLIDILWRQDIDLGVSREVFDFSQRRKEYELEKQKKLEKERQE
  QLQKEQEKAFFAQLQLDEETGEFLPIQPAQHIQSETSGSANYSQVAHIPKSDALYFDDCM
  QLLAQTFPFVDDNEVSSATFQSLVPDIPGHIESPVFIATNQAQSPETSVAQVAPVDLDGM
  QQDIEQVWEELLSIPELQCLNIENDKLVETTMVPSPEAKLTEVDNYHFYSSIPSMEKEVG
  NCSPHFLNAFEDSFSSILSTEDPNQLTVNSLNSDATVNTDFGDEFYSAFIAEPSISNSMP
  SPATLSHSLSELLNGPIDVSDLSLCKAFNQNHPESTAEFNDSDSGISLNTSPSVASPEHS
  VESSSYGDTLLGLSDSEVEELDSAPGSVKQNGPKTPVHSSGDMVQPLSPSQGQSTHVHDA
  QCENTPEKELPVSPGHRKTPFTKDKHSSRLEAHLTRDELRAKALHIPFPVEKIINLPVVD
  FNEMMSKEQFNEAQLALIRDIRRRGKNKVAAQNCRKRKLENIVELEQDLDHLKDEKEKLL
  KEKGENDKSLHLLKKQLSTLYLEVFSMLRDEDGKPYSPSEYSLQQTRDGNVFLVPKSKKP
  DVKKN
• 3D-structure: PDB ID: 7X5E; Classification: Transcription/dna; Method: X-ray diffraction; Resolution: 2.30 Å
• Function: Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response (ARE) elements present in the promoter region of many cytoprotective genes, such as phase 2 detoxifying enzymes, and promotes their expression, thereby neutralizing reactive electrophiles. In normal conditions, ubiquitinated and degraded in the cytoplasm by the BCR(KEAP1) complex. In response to oxidative stress, electrophile metabolites inhibit activity of the BCR(KEAP1) complex, promoting nuclear accumulation of NFE2L2/NRF2, heterodimerization with one of the small Maf proteins and binding to ARE elements of cytoprotective target genes. The NFE2L2/NRF2 pathway is also activated in response to selective autophagy: autophagy promotes interaction between KEAP1 and SQSTM1/p62 and subsequent inactivation of the BCR(KEAP1) complex, leading to NFE2L2/NRF2 nuclear accumulation and expression of cytoprotective genes. May also be involved in the transcriptional activation of genes of the beta-globin cluster by mediating enhancer activity of hypersensitive site 2 of the beta-globin locus control region. Plays also an important role in the regulation of the innate immune response and antiviral cytosolic DNA sensing. It is a critical regulator of the innate immune response and survival during sepsis by maintaining redox homeostasis and restraint of the dysregulation of proinflammatory signaling pathways like MyD88-dependent and -independent and TNF-alpha signaling. Suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription and the induction of IL6. Binds to the proximity of proinflammatory genes in macrophages and inhibits RNA Pol II recruitment. The inhibition is independent of the NRF2-binding motif and reactive oxygen species level. Represses antiviral cytosolic DNA sensing by suppressing the expression of the adapter protein STING1 and decreasing responsiveness to STING1 agonists while increasing susceptibility to infection with DNA viruses. Once activated, limits the release of pro-inflammatory cytokines in response to human coronavirus SARS-CoV-2 infection and to virus-derived ligands through a mechanism that involves inhibition of IRF3 dimerization. Also inhibits both SARS-CoV-2 replication, as well as the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism.
• Uniprot ID: NF2L2_HUMAN
• Ensembl ID: ENSG00000116044
• HGNC ID: HGNC:7782

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Cholangiocarcinoma [ICD-11: 2C12.0] [1]

• Sensitive Disease: Cholangiocarcinoma [ICD-11: 2C12.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Liver cancer [ICD-11: 2C12]
• The Specified Disease: Liver cancer
• The Studied Tissue: Liver tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.05E-01; Fold-change: -1.68E-02; Z-score: -5.21E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: KkU-100 cells; Gallbladder; Homo sapiens (Human); CVCL_3996
• In Vitro Model: KkU-M156 cells; Gallbladder; Homo sapiens (Human); CVCL_M260
• In Vitro Model: KkU-M213 cells; Gallbladder; Homo sapiens (Human); CVCL_M261
• In Vitro Model: KkU-M214 cells; Gallbladder; Homo sapiens (Human); CVCL_M264
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Acri-dine orange and ethidium bromide (AO/EB) fluorescent dyes assay
• Mechanism Description: Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor regulating antioxidant, cytoprotective, and metabolic enzymes, plays important roles in drug resistance and proliferation in cancer cells. Nrf2 mRNA expression of kkU-M156 and kkU-100 cells, representatives of low and high-Nrf2-expressing CCA cells, were silenced using siRNA. After knockdown of Nrf2, the sensitivity of those cells to the cytotoxicity of cisplatin (Cis) was enhanced in association with the increased release of AIF and downregulation of Bcl-xl in both cells.

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.2] [7]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Nrf2 signaling pathway; Activation; hsa05208
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Bioinformatics analysis and luciferase assays ofNrf2-3'-untranslated region-based reporter constructor indicated that Nrf2 was the direct target gene of miR-340, miR-340 mimics suppressing Nrf2-dependent antioxidant pathway and enhancing the sensitivity of HepG2/CDDP cells to cisplatin. Interestingly, transfection with miR-340 mimics combined with miR-340 inhibitorsreactivated the Nrf2 related pathway and restored the resistance of HepG2/CDDP cells to CDDP. Collectively,the results first suggested that lower expression of miR-340 is involved in the development of CDDP resistancein hepatocellular carcinoma cell line, at least partly due to regulating Nrf2-dependent antioxidant pathway.

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [ICD-11: 2C25.5] [2]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Lung cancer
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.75E-12; Fold-change: -7.61E-02; Z-score: -7.11E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Nrf2 signaling pathway; Inhibition; hsa05208
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Cos-7 cells; Lung; Homo sapiens (Human); CVCL_0224
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-144-3p promotes cisplatin sensitivity by downregulating Nrf2 in lung cancer cells.

Disease Class: Esophageal squamous cell carcinoma [ICD-11: 2B70.3] [6]

• Resistant Disease: Esophageal squamous cell carcinoma [ICD-11: 2B70.3]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: TE-1 cells; Esophagus; Homo sapiens (Human); CVCL_1759
• Experiment for Molecule Alteration: RNA pull-down assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: TUG1 promoted cell resistance to DDP, at least in part, through upregulating Nrf2.

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Head and neck squamous cell carcinoma [ICD-11: 2D42.0] [5]

• Metabolic Type: Redox metabolism
• Resistant Disease: Head and neck squamous cell carcinoma [ICD-11: 2D42.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HN30 cells; Nasopharyngeal; Homo sapiens (Human); CVCL_5525
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell colony formation assay
• Mechanism Description: The CDDP-resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance.

Arsenic trioxide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [ICD-11: 2C25.5] [3]

• Resistant Disease: Lung cancer [ICD-11: 2C25.5]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Nrf2 signaling pathway; Activation; hsa05208
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: MTT Assay
• Mechanism Description: miR155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. miR155 mediated ATO resistance by upregulating the Nrf2 signaling pathway, but downregulating cellular apoptosis in lung cancer cells.

Disease Class: Acute promyelocytic leukemia [ICD-11: 2A60.2] [4]

• Resistant Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Resistant Drug: Arsenic trioxide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxidative stress response signaling pathway; Regulation; N.A.
• In Vitro Model: MV4-11 ATO-R C4 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: MV4-11 ATO-R C6 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: Apoptosis analysis; Intracellular ROS assay; Flow cytometry assay
• Mechanism Description: We examined the effects of molecular/pharmacological suppression of?NRF2?on acquired ATO resistance in the?FLT3-ITD?mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2?expression, nuclear localization, and upregulation of bonafide?NRF2 targets. Molecular inhibition of?NRF2?in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.

Clinical Trial Drug(s) 1 drug(s) in total

APR-246

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung adenocarcinoma [ICD-11: 2C25.0] [8]

• Sensitive Disease: Lung adenocarcinoma [ICD-11: 2C25.0]
• Sensitive Drug: APR-246
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: NRF2/SLC7A11/GSH signalling pathway; Regulation; N.A.
• In Vitro Model: H460/CIS cells; Lung; Homo sapiens (Human); CVCL_A9CH
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: MTT assay; Colony formation assay; Apoptosis assay
• Mechanism Description: In this study, we identify NADPH metabolism and reactive oxygen species (ROS) levels as the main causes accounting for cisplatin resistance. Based on a small panel consisting of common chemotherapy drugs or compounds, APR-246 is proved to be an effective compound targeting cisplatin-resistant NSCLC cells. APR-246 specially inhibits proliferation and colony formation of cisplatin-resistant cells. In details, APR-246 can significantly cause G0/G1 accumulation and S phase arrest of cisplatin resistant cells and gives rise to severe mitochondria dysfunction as well as elevated apoptosis. Further study proves that it is the aberrant ROS levels as well as NRF2/SLC7A11/GSH axis dysfunction accounting for the specific antitumor effects of APR-246. Scavenging ROS with N-acetylcysteine (NAC) disrupts the inhibitory effect of APR-246 on cisplatin-resistant cells.

Investigative Drug(s) 1 drug(s) in total

ATO-Digoxin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Acute promyelocytic leukemia [ICD-11: 2A60.2] [4]

• Sensitive Disease: Acute promyelocytic leukemia [ICD-11: 2A60.2]
• Sensitive Drug: ATO-Digoxin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Oxidative stress response signaling pathway; Regulation; N.A.
• In Vivo Model: MV4-11 ATO-R C6 xenograft mice; Mus musculus
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: In-vivo drug treatment assay
• Mechanism Description: We examined the effects of molecular/pharmacological suppression of?NRF2?on acquired ATO resistance in the?FLT3-ITD?mutant AML cell line (MV4-11-ATO-R). ATO-R cells showed increased NRF2?expression, nuclear localization, and upregulation of bonafide?NRF2 targets. Molecular inhibition of?NRF2?in this resistant cell line improved ATO sensitivity in vitro. Digoxin treatment lowered p-AKT expression, abrogating nuclear NRF2 localization and sensitizing cells to ATO. However, digoxin and ATO did not sensitize non-ITD AML cell line THP1 with high NRF2 expression. Digoxin decreased leukemic burden and prolonged survival in MV4-11 ATO-R xenograft mice. We establish that altering NRF2 expression may reverse acquired ATO resistance in FLT3-ITD AML.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Esophageal cancer [ICD-11: 2B70]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Esophagus
• The Specified Disease: Esophageal cancer
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.24E-07; Fold-change: -1.44E+00; Z-score: -6.31E+00

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.05E-01; Fold-change: -1.70E-01; Z-score: -2.16E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.14E-03; Fold-change: 2.57E-01; Z-score: 2.94E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 6.72E-01; Fold-change: -1.28E-01; Z-score: -1.86E-01

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.75E-12; Fold-change: -2.80E-01; Z-score: -5.80E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 5.13E-02; Fold-change: 7.37E-02; Z-score: 9.94E-02

References

• Ref 1: Nrf2 inhibition sensitizes cholangiocarcinoma cells to cytotoxic and antiproliferative activities of chemotherapeutic agents. Tumour Biol. 2016 Aug;37(8):11495-507. doi: 10.1007/s13277-016-5015-0. Epub 2016 Mar 25.
• Ref 2: miR 144 3p regulates the resistance of lung cancer to cisplatin by targeting Nrf2. Oncol Rep. 2018 Dec;40(6):3479-3488. doi: 10.3892/or.2018.6772. Epub 2018 Oct 8.
• Ref 3: miR-155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. Sci Rep. 2017 Sep 22;7(1):12155. doi: 10.1038/s41598-017-06061-x.
• Ref 4: Inhibition of NRF2 signaling overcomes acquired resistance to arsenic trioxide in FLT3-mutated Acute Myeloid Leukemia. Ann Hematol. 2024 Jun;103(6):1919-1929.
• Ref 5: Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma. Clin Cancer Res. 2023 Apr 3;29(7):1344-1359.
• Ref 6: LncRNA TUG1 promotes cisplatin resistance in esophageal squamous cell carcinoma cells by regulating Nrf2. Acta Biochim Biophys Sin (Shanghai). 2019 Aug 5;51(8):826-833. doi: 10.1093/abbs/gmz069.
• Ref 7: miR-340 reverses cisplatin resistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway. Asian Pac J Cancer Prev. 2014;15(23):10439-44. doi: 10.7314/apjcp.2014.15.23.10439.
• Ref 8: Aberrant ROS Served as an Acquired Vulnerability of Cisplatin-Resistant Lung Cancer. Oxid Med Cell Longev. 2022 Jun 20;2022:1112987.