Molecule Information

General Information of the Molecule (ID: Mol04168)

• Name: Tumor necrosis factor receptor-associated protein 1 (TRAP1) ,Homo sapiens
• Synonyms: Heat shock protein family C member 5; TNFR-associated protein 1; Tumor necrosis factor type 1 receptor-associated protein
• Molecule Type: Protein
• Gene Name: TRAP1
• Gene ID: 10131
• Location: chr16:3651639-3717553[-]
• Sequence:
  MARELRALLLWGRRLRPLLRAPALAAVPGGKPILCPRRTTAQLGPRRNPAWSLQAGRLFS
  TQTAEDKEEPLHSIISSTESVQGSTSKHEFQAETKKLLDIVARSLYSEKEVFIRELISNA
  SDALEKLRHKLVSDGQALPEMEIHLQTNAEKGTITIQDTGIGMTQEELVSNLGTIARSGS
  KAFLDALQNQAEASSKIIGQFGVGFYSAFMVADRVEVYSRSAAPGSLGYQWLSDGSGVFE
  IAEASGVRTGTKIIIHLKSDCKEFSSEARVRDVVTKYSNFVSFPLYLNGRRMNTLQAIWM
  MDPKDVREWQHEEFYRYVAQAHDKPRYTLHYKTDAPLNIRSIFYVPDMKPSMFDVSRELG
  SSVALYSRKVLIQTKATDILPKWLRFIRGVVDSEDIPLNLSRELLQESALIRKLRDVLQQ
  RLIKFFIDQSKKDAEKYAKFFEDYGLFMREGIVTATEQEVKEDIAKLLRYESSALPSGQL
  TSLSEYASRMRAGTRNIYYLCAPNRHLAEHSPYYEAMKKKDTEVLFCFEQFDELTLLHLR
  EFDKKKLISVETDIVVDHYKEEKFEDRSPAAECLSEKETEELMAWMRNVLGSRVTNVKVT
  LRLDTHPAMVTVLEMGAARHFLRMQQLAKTQEERAQLLQPTLEINPRHALIKKLNQLRAS
  EPGLAQLLVDQIYENAMIAAGLVDDPRAMVGRLNELLVKALERH
• 3D-structure: PDB ID: 6XG6; Classification: Chaperone; Method: Electron microscopy; Resolution: 3.20 Å
• Function: Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, downstream of PINK1 and mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA. .
• Uniprot ID: TRAP1_HUMAN
• Ensembl ID: ENSG00000126602
• HGNC ID: HGNC:16264

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) 2 drug(s) in total

Cetuximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Colorectal carcinomas [ICD-11: 2B91.Y] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal carcinomas [ICD-11: 2B91.Y]
• Resistant Drug: Cetuximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Human RAS-wild-type mCRCs; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: 18F-FDG uptake
• Mechanism Description: TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.

Disease Class: Colorectal carcinomas [ICD-11: 2B91.Y] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal carcinomas [ICD-11: 2B91.Y]
• Resistant Drug: Cetuximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Human RAS-wild-type mCRCs; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Stable tumors assay
• Mechanism Description: TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.

Disease Class: Colorectal carcinomas [ICD-11: 2B91.Y] [1]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Colorectal carcinomas [ICD-11: 2B91.Y]
• Resistant Drug: Cetuximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: RAS-wild-type Caco2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: RAS-wild-type NCIH508 cells; Colon; Homo sapiens (Human); CVCL_1564
• Experiment for Molecule Alteration: Western blot analysis
• Mechanism Description: TRAP1 is a determinant of metabolic rewiring in human CRCs by the modulation of PFK1 activity/stability and favors resistance to EGFR inhibitors through the regulation of glycolytic metabolism.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP1 inversely correlates with stage and grade and directly correlates with survival.

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [2]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP2 inversely correlates with stage and grade and directly correlates with survival.

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

Antimycin A

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Ovarian cancer [ICD-11: 2C73.0] [2]

• Metabolic Type: Mitochondrial metabolism
• Sensitive Disease: Ovarian cancer [ICD-11: 2C73.0]
• Sensitive Drug: Antimycin A
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT-116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: Hela cells; Cervix uteri; Homo sapiens (Human); CVCL_0030
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Accordingly, drug-resistant ovarian cancer cells show high levels of complex III components and high sensitivity to complex III inhibitory drug antimycin A.

References

• Ref 1: TRAP1 enhances Warburg metabolism through modulation of PFK1 expression/activity and favors resistance to EGFR inhibitors in human colorectal carcinomas. Mol Oncol. 2020 Dec;14(12):3030-3047.
• Ref 2: Regulation of mitochondrial complex III activity and assembly by TRAP1 in cancer cells. Cancer Cell Int. 2022 Dec 12;22(1):402.