Molecule Information

General Information of the Molecule (ID: Mol04038)

• Name: Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) ,Homo sapiens
• Synonyms: IGF-II mRNA-binding protein 3; KH domain-containing protein overexpressed in cancer; VICKZ family member 3
• Molecule Type: Protein
• Gene Name: IGF2BP3
• Gene ID: 10643
• Location: chr7:23310209-23470491[-]
• Sequence:
  MNKLYIGNLSENAAPSDLESIFKDAKIPVSGPFLVKTGYAFVDCPDESWALKAIEALSGK
  IELHGKPIEVEHSVPKRQRIRKLQIRNIPPHLQWEVLDSLLVQYGVVESCEQVNTDSETA
  VVNVTYSSKDQARQALDKLNGFQLENFTLKVAYIPDEMAAQQNPLQQPRGRRGLGQRGSS
  RQGSPGSVSKQKPCDLPLRLLVPTQFVGAIIGKEGATIRNITKQTQSKIDVHRKENAGAA
  EKSITILSTPEGTSAACKSILEIMHKEAQDIKFTEEIPLKILAHNNFVGRLIGKEGRNLK
  KIEQDTDTKITISPLQELTLYNPERTITVKGNVETCAKAEEEIMKKIRESYENDIASMNL
  QAHLIPGLNLNALGLFPPTSGMPPPTSGPPSAMTPPYPQFEQSETETVHLFIPALSVGAI
  IGKQGQHIKQLSRFAGASIKIAPAEAPDAKVRMVIITGPPEAQFKAQGRIYGKIKEENFV
  SPKEEVKLEAHIRVPSFAAGRVIGKGGKTVNELQNLSSAEVVVPRDQTPDENDQVVVKIT
  GHFYACQVAQRKIQEILTQVKQHQQQKALQSGPPQSRRK
• 3D-structure: PDB ID: 6FQ1; Classification: Rna binding protein; Method: X-ray diffraction; Resolution: 1.31 Å
• Function: RNA-binding factor that may recruit target transcripts to cytoplasmic protein-RNA complexes (mRNPs). This transcript 'caging' into mRNPs allows mRNA transport and transient storage. It also modulates the rate and location at which target transcripts encounter the translational apparatus and shields them from endonuclease attacks or microRNA-mediated degradation. Preferentially binds to N6- methyladenosine (m6A)-containing mRNAs and increases their stability (PubMed:29476152). Binds to the 3'-UTR of CD44 mRNA and stabilizes it, hence promotes cell adhesion and invadopodia formation in cancer cells. Binds to beta-actin/ACTB and MYC transcripts. Increases MYC mRNA stability by binding to the coding region instability determinant (CRD) and binding is enhanced by m6A-modification of the CRD (PubMed:29476152). Binds to the 5'-UTR of the insulin-like growth factor 2 (IGF2) mRNAs. .
• Uniprot ID: IF2B3_HUMAN
• Ensembl ID: ENSG00000136231
• HGNC ID: HGNC:28868

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) 3 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: 1.38E-05; Fold-change: 6.29E-01; Z-score: 4.51E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice , with PC-9/GR cell lines; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B5 axis in NSCLC.

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: 1.38E-05; Fold-change: 6.29E-01; Z-score: 4.51E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice , with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B4 axis in NSCLC.

Gefitinib

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: Gefitinib
• 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: 1.38E-05; Fold-change: 6.29E-01; Z-score: 4.51E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice , with PC-9/GR cell lines; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B3 axis in NSCLC.

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: Gefitinib
• 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: 1.38E-05; Fold-change: 6.29E-01; Z-score: 4.51E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude mice , with fresh tissue from patient; Mice
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Furthermore, we revealed that targeting IGF2BP3 can markedly enhance the sensitivity of TKIs in NSCLC and this effect was strongly dependent on the coordinated induction of COX6B2, a key downstream target of IGF2BP3 in mitochondrial OXPHOS energy production. Overall, our study revealed a novel mechanism of TKI resistance involved in IGF2BP3-dependent cross-talk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis in NSCLC.

Lenvatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Lactylation; K76
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: HCC patients; Homo Sapiens
• Experiment for Molecule Alteration: Liquid chromatography mass spectrometry (LC-MS)
• Experiment for Drug Resistance: Modified response evaluation criteria in solid tumors (mRECIST)
• Mechanism Description: This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [2]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: Lenvatinib
• Molecule Alteration: Lactylation; K76
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Hydrodynamic transfection mouse model; Mice
• Experiment for Molecule Alteration: Liquid chromatography?mass spectrometry (LC?MS)
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [2]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Lenvatinib
• Molecule Alteration: Lactylation; K76
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Orthotopic HCC model with the glycolysis inhibitor 2-DG; Homo Sapiens
• Experiment for Molecule Alteration: Liquid chromatography mass spectrometry (LC-MS)
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

Disease Class: Hepatocellular carcinoma [ICD-11: 2C12.02] [2]

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Sensitive Drug: Lenvatinib
• Molecule Alteration: Lactylation; K76
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IGF2BP3 knockdown Hep3B-LR cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vitro Model: IGF2BP3 knockdown Huh7-LR cells; Liver; Homo sapiens (Human); CVCL_0336
• Experiment for Molecule Alteration: Liquid chromatography?mass spectrometry (LC?MS)
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: This study reveals that in lenvatinib-resistant hepatocellular carcinoma, increased glycolysis results in lactate accumulation and lysine lactylation of IGF2BP3, which increase the expression of PCK2 and NRF2. This leads to a reprogramming of serine metabolism, S-adenosylmethionine (SAM) production, RNA m6A modification, and the antioxidant system. The IGF2BP3 lactylation-PCK2-SAM-m6A loop sustains the upregulation of PCK2 and NRF2 expression and ultimately confers lenvatinib resistance.

References

• Ref 1: Metabolic Reprogramming Driven by IGF2BP3 Promotes Acquired Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer. Cancer Res. 2023 Jul 5;83(13):2187-2207.
• Ref 2: Lactylation-Driven IGF2BP3-Mediated Serine Metabolism Reprogramming and RNA m6A-Modification Promotes Lenvatinib Resistance in HCC. Adv Sci (Weinh). 2024 Dec;11(46):e2401399.