Molecule Information

General Information of the Molecule (ID: Mol04051)

• Name: Nuclear receptor coactivator 4 (NCOA4) ,Homo sapiens
• Synonyms: Androgen receptor coactivator 70 kDa protein; Androgen receptor-associated protein of 70 kDa; Ferritin cargo receptor NCOA4; Ret-activating protein ELE1
• Molecule Type: Protein
• Gene Name: NCOA4
• Gene ID: 8031
• Location: chr10:46005088-46030623[-]
• Sequence:
  MNTFQDQSGSSSNREPLLRCSDARRDLELAIGGVLRAEQQIKDNLREVKAQIHSCISRHL
  ECLRSREVWLYEQVDLIYQLKEETLQQQAQQLYSLLGQFNCLTHQLECTQNKDLANQVSV
  CLERLGSLTLKPEDSTVLLFEADTITLRQTITTFGSLKTIQIPEHLMAHASSANIGPFLE
  KRGCISMPEQKSASGIVAVPFSEWLLGSKPASGYQAPYIPSTDPQDWLTQKQTLENSQTS
  SRACNFFNNVGGNLKGLENWLLKSEKSSYQKCNSHSTTSSFSIEMEKVGDQELPDQDEMD
  LSDWLVTPQESHKLRKPENGSRETSEKFKLLFQSYNVNDWLVKTDSCTNCQGNQPKGVEI
  ENLGNLKCLNDHLEAKKPLSTPSMVTEDWLVQNHQDPCKVEEVCRANEPCTSFAECVCDE
  NCEKEALYKWLLKKEGKDKNGMPVEPKPEPEKHKDSLNMWLCPRKEVIEQTKAPKAMTPS
  RIADSFQVIKNSPLSEWLIRPPYKEGSPKEVPGTEDRAGKQKFKSPMNTSWCSFNTADWV
  LPGKKMGNLSQLSSGEDKWLLRKKAQEVLLNSPLQEEHNFPPDHYGLPAVCDLFACMQLK
  VDKEKWLYRTPLQM
• 3D-structure: PDB ID: 8QU9; Classification: Metal transport; Method: Electron microscopy; Resolution: 2.88 Å
• Function: Cargo receptor for the autophagic turnover of the iron- binding ferritin complex, playing a central role in iron homeostasis (PubMed:25327288, PubMed:26436293). Acts as an adapter for delivery of ferritin to lysosomes and autophagic degradation of ferritin, a process named ferritinophagy (PubMed:25327288, PubMed:26436293). Targets the iron-binding ferritin complex to autolysosomes following starvation or iron depletion (PubMed:25327288). Ensures efficient erythropoiesis, possibly by regulating hemin-induced erythroid differentiation (PubMed:26436293). In some studies, has been shown to enhance the androgen receptor AR transcriptional activity as well as acting as ligand-independent coactivator of the peroxisome proliferator-activated receptor (PPAR) gamma (PubMed:10347167, PubMed:8643607). Another study shows only weak behavior as a coactivator for the androgen receptor and no alteration of the ligand responsiveness of the AR (PubMed:10517667). Binds to DNA replication origins, binding is not restricted to sites of active transcription and may likely be independent from the nuclear receptor transcriptional coactivator function (PubMed:24910095). May inhibit activation of DNA replication origins, possibly by obstructing DNA unwinding via interaction with the MCM2-7 complex (PubMed:24910095). .
• Uniprot ID: NCOA4_HUMAN
• Ensembl ID: ENSG00000266412
• HGNC ID: HGNC:7671

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

Drug Resistance Data Categorized by Drug

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

Osimertinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Non-small cell lung carcinoma [ICD-11: 2C25.Y] [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Non-small cell lung carcinoma [ICD-11: 2C25.Y]
• Resistant Drug: Osimertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Lung cancer [ICD-11: 2C25]
• The Specified Disease: Non-small cell lung carcinoma
• The Studied Tissue: Lung tissue
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.00E-02; Fold-change: 6.78E-02; Z-score: 1.70E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: H1975 cells; Lung; Homo sapiens (Human); CVCL_B0JT
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: PI/Annexin V apoptosis assay
• Mechanism Description: Mechanically, Osi treatment induces an elevation of NCOA4, a key protein of ferritinophagy, which maintains the synthesis of iron-sulfur cluster (ISC) proteins of electron transport chain and OXPHOS. Additionally, active ISC protein synthesis in adaptive-resistant cells significantly increases the sensitivity to copper ions. Combining Osi with elesclomol, a copper ion ionophore, significantly increases the efficacy of Osi, with no additional toxicity. Altogether, this study reveals the mechanisms of NCOA4-mediated ferritinophagy in Osi adaptive resistance and introduces a promising new therapy of combining copper ionophores to improve its initial efficacy.

References

• Ref 1: Ferritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer. Nat Commun. 2024 May 17;15(1):4195.