Molecule Information

General Information of the Molecule (ID: Mol04112)

• Name: Glucose-regulated protein 75 (GRP75) ,Homo sapiens
• Synonyms: 75 kDa glucose-regulated protein; Heat shock 70 kDa protein 9; Heat shock protein family A member 9; Mortalin; Peptide-binding protein 74
• Molecule Type: Protein
• Gene Name: HSPA9
• Gene ID: 3313
• Location: chr5:138553756-138575675[-]
• Sequence:
  MISASRAAAARLVGAAASRGPTAARHQDSWNGLSHEAFRLVSRRDYASEAIKGAVVGIDL
  GTTNSCVAVMEGKQAKVLENAEGARTTPSVVAFTADGERLVGMPAKRQAVTNPNNTFYAT
  KRLIGRRYDDPEVQKDIKNVPFKIVRASNGDAWVEAHGKLYSPSQIGAFVLMKMKETAEN
  YLGHTAKNAVITVPAYFNDSQRQATKDAGQISGLNVLRVINEPTAAALAYGLDKSEDKVI
  AVYDLGGGTFDISILEIQKGVFEVKSTNGDTFLGGEDFDQALLRHIVKEFKRETGVDLTK
  DNMALQRVREAAEKAKCELSSSVQTDINLPYLTMDSSGPKHLNMKLTRAQFEGIVTDLIR
  RTIAPCQKAMQDAEVSKSDIGEVILVGGMTRMPKVQQTVQDLFGRAPSKAVNPDEAVAIG
  AAIQGGVLAGDVTDVLLLDVTPLSLGIETLGGVFTKLINRNTTIPTKKSQVFSTAADGQT
  QVEIKVCQGEREMAGDNKLLGQFTLIGIPPAPRGVPQIEVTFDIDANGIVHVSAKDKGTG
  REQQIVIQSSGGLSKDDIENMVKNAEKYAEEDRRKKERVEAVNMAEGIIHDTETKMEEFK
  DQLPADECNKLKEEISKMRELLARKDSETGENIRQAASSLQQASLKLFEMAYKKMASERE
  GSGSSGTGEQKEDQKEEKQ
• Function: Chaperone protein which plays an important role in mitochondrial iron-sulfur cluster (ISC) biogenesis. Interacts with and stabilizes ISC cluster assembly proteins FXN, NFU1, NFS1 and ISCU (PubMed:26702583). Regulates erythropoiesis via stabilization of ISC assembly (PubMed:21123823, PubMed:26702583). May play a role in cell cycle regulation via its interaction with and promotion of degradation of TP53 (PubMed:24625977, PubMed:26634371). May play a role in the control of cell proliferation and cellular aging (By similarity). Molecular adapter that regulates mitochondrial calcium-dependent apoptosis by coupling two calcium channels, ITPR1 and VDAC1, at the mitochondria-associated endoplasmic reticulum (ER) membrane to facilitate calcium transport from the ER lumen to the mitochondria intermembrane space, thus providing calcium for the downstream calcium channel MCU that directly releases it into mitochondria matrix (By similarity). .
• Uniprot ID: GRP75_HUMAN
• Ensembl ID: ENSG00000113013
• HGNC ID: HGNC:5244

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

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SGC-7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: IC50 assay
• Mechanism Description: Knockdown of GRP75 abolished the maintenance of mitochondrial membrane potential (MMP) and inhibited the nuclear factor erythroid-2-related factor 2 (NRF2), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), hypoxia-inducible factor 1alpha (HIF-1alpha), and c-myc, which resulted in blocking the activation of their downstream targets. These processes attenuated the anti-oxidation/apoptosis abilities and altered the metabolic reprogramming in SGC7901CR cells, leading to re-sensitizing these cells to cisplatin. However, overexpression of GRP75 in SGC7901 cells caused the opposite effects. A xenografts model confirmed the abovementioned results. In GC patients receiving platinum chemotherapy and a meta-analysis, a high level of GRP75 was positively associated with aggressive characteristics and poor prognosis including but not limited to gastrointestinal cancers, and was an independent predictor for overall survival.

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

27-Hydroxycholesterol

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: Redox metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: 27-Hydroxycholesterol
• Molecule Alteration: Activity; activation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75).

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

• Metabolic Type: Redox metabolism
• Resistant Disease: Hepatocellular carcinoma [ICD-11: 2C12.02]
• Resistant Drug: 27-Hydroxycholesterol
• Molecule Alteration: Activity; activation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: HepG2 cells, BALB/c nude mice; Mice
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: we found that by inducing an increase in oxidative stress signalling, 27HC activated glucose-regulated protein 75 (GRP75).

References

• Ref 1: Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming. Cell Death Discov. 2021 Jun 11;7(1):140.
• Ref 2: 27-Hydroxycholesterol is a specific factor in the neoplastic microenvironment of HCC that causes MDR via GRP75 regulation of the redox balance and metabolic reprogramming. Cell Biol Toxicol. 2022 Apr;38(2):311-324.