Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7JSZLB)

• DOT Name: 10 kDa heat shock protein, mitochondrial (HSPE1)
• Synonyms: Hsp10; 10 kDa chaperonin; Chaperonin 10; CPN10; Early-pregnancy factor; EPF
• Gene Name: HSPE1
• UniProt ID: CH10_HUMAN
• PDB ID: 4PJ1; 6HT7; 6MRC; 6MRD; 8G7N; 8G7O
• Pfam ID: PF00166
• Sequence:
  MAGQAFRKFLPLFDRVLVERSAAETVTKGGIMLPEKSQGKVLQATVVAVGSGSKGKGGEI
  QPVSVKVGDKVLLPEYGGTKVVLDDKDYFLFRDGDILGKYVD
• Function: Co-chaperonin implicated in mitochondrial protein import and macromolecular assembly. Together with Hsp60, facilitates the correct folding of imported proteins. May also prevent misfolding and promote the refolding and proper assembly of unfolded polypeptides generated under stress conditions in the mitochondrial matrix. The functional units of these chaperonins consist of heptameric rings of the large subunit Hsp60, which function as a back-to-back double ring. In a cyclic reaction, Hsp60 ring complexes bind one unfolded substrate protein per ring, followed by the binding of ATP and association with 2 heptameric rings of the co-chaperonin Hsp10. This leads to sequestration of the substrate protein in the inner cavity of Hsp60 where, for a certain period of time, it can fold undisturbed by other cell components. Synchronous hydrolysis of ATP in all Hsp60 subunits results in the dissociation of the chaperonin rings and the release of ADP and the folded substrate protein (Probable).
• Reactome Pathway: RHOG GTPase cycle (R-HSA-9013408)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	10 kDa heat shock protein, mitochondrial (HSPE1) decreases the response to substance of Cisplatin.	[28]
PEITC	DMOMN31	Phase 2	10 kDa heat shock protein, mitochondrial (HSPE1) affects the binding of PEITC.	[29]

29 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[2]
Marinol	DM70IK5	Approved	Marinol decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[9]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[11]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[12]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[13]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[14]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[15]
Dihydroxyacetone	DMM1LG2	Approved	Dihydroxyacetone increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[16]
Raltitrexed	DMT9K8G	Approved	Raltitrexed increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[17]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[20]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[22]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[23]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[24]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[25]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[26]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Investigative	(E)-4-(3,5-dimethoxystyryl)phenol decreases the expression of 10 kDa heat shock protein, mitochondrial (HSPE1).	[27]

References

• [1] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [2] Comparison of the gene expression profiles of monocytic versus granulocytic lineages of HL-60 leukemia cell differentiation by DNA microarray analysis. Life Sci. 2003 Aug 15;73(13):1705-19. doi: 10.1016/s0024-3205(03)00515-0.
• [3] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [4] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] Differential protein expression of peroxiredoxin I and II by benzo(a)pyrene and quercetin treatment in 22Rv1 and PrEC prostate cell lines. Toxicol Appl Pharmacol. 2007 Apr 15;220(2):197-210. doi: 10.1016/j.taap.2006.12.030. Epub 2007 Jan 9.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Gene expression changes in human small airway epithelial cells exposed to Delta9-tetrahydrocannabinol. Toxicol Lett. 2005 Aug 14;158(2):95-107.
• [10] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [11] 5-Fluorouracil: identification of novel downstream mediators of tumour response. Anticancer Res. 2004 Mar-Apr;24(2A):417-23.
• [12] Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study. J Nutr Sci. 2016 Apr 26;5:e17. doi: 10.1017/jns.2016.8. eCollection 2016.
• [13] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [16] The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594. doi: 10.1016/j.redox.2020.101594. Epub 2020 May 29.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Comparative proteomics reveals concordant and discordant biochemical effects of caffeine versus epigallocatechin-3-gallate in human endothelial cells. Toxicol Appl Pharmacol. 2019 Sep 1;378:114621. doi: 10.1016/j.taap.2019.114621. Epub 2019 Jun 10.
• [19] BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012 Oct 4;120(14):2843-52.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [22] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
• [23] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [24] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [25] Cytotoxicity and gene array analysis of alveolar epithelial A549 cells exposed to paraquat. Chem Biol Interact. 2010 Dec 5;188(3):427-36.
• [26] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [27] Proteomic identification of pterostilbene-mediated anticancer activities in HepG2 cells. Chem Res Toxicol. 2014 Jul 21;27(7):1243-52. doi: 10.1021/tx5001392. Epub 2014 Jul 1.
• [28] Identification by functional cloning from a retroviral cDNA library of cDNAs for ribosomal protein L36 and the 10-kDa heat shock protein that confer cisplatin resistance. Mol Pharmacol. 2006 Apr;69(4):1383-8. doi: 10.1124/mol.105.017525. Epub 2006 Jan 4.
• [29] Identification of potential protein targets of isothiocyanates by proteomics. Chem Res Toxicol. 2011 Oct 17;24(10):1735-43. doi: 10.1021/tx2002806. Epub 2011 Aug 26.