Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTANQA6G)

• DOT Name: Transmembrane protein 14A (TMEM14A)
• Gene Name: TMEM14A
• Related Disease:
  Epithelial ovarian cancer
  Estrogen-receptor positive breast cancer
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Ovarian serous cystadenocarcinoma
  Acute myelogenous leukaemia
• UniProt ID: TM14A_HUMAN
• PDB ID: 2LOO; 2LOP
• Pfam ID: PF03647
• Sequence:
  MDLIGFGYAALVTFGSIFGYKRRGGVPSLIAGLFVGCLAGYGAYRVSNDKRDVKVSLFTA
  FFLATIMGVRFKRSKKIMPAGLVAGLSLMMILRLVLLLL
• Function: Inhibits apoptosis via negative regulation of the mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway.
• Tissue Specificity: Expressed at significantly higher levels in ovarian cancer tissues than in normal tissues (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[1]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Genetic Variation	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[1]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[1]
Ovarian serous cystadenocarcinoma	DISMYAWR	Strong	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Transmembrane protein 14A (TMEM14A) affects the response to substance of Doxorubicin.	[20]
Vinblastine	DM5TVS3	Approved	Transmembrane protein 14A (TMEM14A) affects the response to substance of Vinblastine.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Transmembrane protein 14A (TMEM14A).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Transmembrane protein 14A (TMEM14A).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Transmembrane protein 14A (TMEM14A).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Transmembrane protein 14A (TMEM14A).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Transmembrane protein 14A (TMEM14A).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Transmembrane protein 14A (TMEM14A).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Transmembrane protein 14A (TMEM14A).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Transmembrane protein 14A (TMEM14A).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Transmembrane protein 14A (TMEM14A).	[13]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Transmembrane protein 14A (TMEM14A).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Transmembrane protein 14A (TMEM14A).	[16]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 decreases the expression of Transmembrane protein 14A (TMEM14A).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transmembrane protein 14A (TMEM14A).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Transmembrane protein 14A (TMEM14A).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Transmembrane protein 14A (TMEM14A).	[19]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Transmembrane protein 14A (TMEM14A).	[15]

References

• [1] Knockdown of TMEM14A expression by RNAi inhibits the proliferation and invasion of human ovarian cancer cells.Biosci Rep. 2016 Feb 19;36(1):e00298. doi: 10.1042/BSR20150258. Print 2016.
• [2] Aromatase inhibitor-associated bone fractures: a case-cohort GWAS and functional genomics.Mol Endocrinol. 2014 Oct;28(10):1740-51. doi: 10.1210/me.2014-1147. Epub 2014 Aug 22.
• [3] Elevation of circular RNA circ_0003645 forecasts unfavorable prognosis and facilitates cell progression via miR-1179/TMEM14A pathway in non-small cell lung cancer.Biochem Biophys Res Commun. 2019 Apr 16;511(4):921-925. doi: 10.1016/j.bbrc.2019.03.011. Epub 2019 Mar 8.
• [4] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] 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.
• [14] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [15] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [16] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [17] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.