Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYZ6BEQ)

• DOT Name: PRA1 family protein 3 (ARL6IP5)
• Synonyms: ADP-ribosylation factor-like protein 6-interacting protein 5; ARL-6-interacting protein 5; Aip-5; Cytoskeleton-related vitamin A-responsive protein; Dermal papilla-derived protein 11; GTRAP3-18; Glutamate transporter EAAC1-interacting protein; JM5; Prenylated Rab acceptor protein 2; Protein JWa; Putative MAPK-activating protein PM27
• Gene Name: ARL6IP5
• Related Disease:
  Breast carcinoma
  Carcinoma of esophagus
  Gastric cancer
  leukaemia
  Leukemia
  Melanoma
  Advanced cancer
  Bladder cancer
  Carcinoma
  Esophageal cancer
  Hereditary diffuse gastric adenocarcinoma
  Immune system disorder
  Metastatic malignant neoplasm
  Neoplasm of esophagus
  Obesity
  Parkinson disease
  Schizophrenia
  Squamous cell carcinoma
  Substance withdrawal syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Gastric neoplasm
  Anemia
  Malaria
  Breast cancer
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Neoplasm
  Polyposis
  Stomach cancer
• UniProt ID: PRAF3_HUMAN
• Pfam ID: PF03208
• Sequence:
  MDVNIAPLRAWDDFFPGSDRFARPDFRDISKWNNRVVSNLLYYQTNYLVVAAMMISIVGF
  LSPFNMILGGIVVVLVFTGFVWAAHNKDVLRRMKKRYPTTFVMVVMLASYFLISMFGGVM
  VFVFGITFPLLLMFIHASLRLRNLKNKLENKMEGIGLKRTPMGIVLDALEQQEEGINRLT
  DYISKVKE
• Function: Regulates intracellular concentrations of taurine and glutamate. Negatively modulates SLC1A1/EAAC1 glutamate transport activity by decreasing its affinity for glutamate in a PKC activity-dependent manner. Plays a role in the retention of SLC1A1/EAAC1 in the endoplasmic reticulum.
• Reactome Pathway: Glutamate Neurotransmitter Release Cycle (R-HSA-210500)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Carcinoma of esophagus	DISS6G4D	Definitive	Genetic Variation	[2]
Gastric cancer	DISXGOUK	Definitive	Altered Expression	[3]
leukaemia	DISS7D1V	Definitive	Genetic Variation	[4]
Leukemia	DISNAKFL	Definitive	Genetic Variation	[4]
Melanoma	DIS1RRCY	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[2]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[6]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[2]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[7]
Immune system disorder	DISAEGPH	Strong	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[9]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[2]
Substance withdrawal syndrome	DISTT24U	Strong	Therapeutic	[13]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[4]
Gastric neoplasm	DISOKN4Y	moderate	Biomarker	[7]
Anemia	DISTVL0C	Disputed	Genetic Variation	[14]
Malaria	DISQ9Y50	Disputed	Genetic Variation	[14]
Breast cancer	DIS7DPX1	Limited	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[15]
Esophageal squamous cell carcinoma	DIS5N2GV	Limited	Altered Expression	[6]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]
Polyposis	DISZSPOK	Limited	Biomarker	[15]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	PRA1 family protein 3 (ARL6IP5) increases the response to substance of Arsenic trioxide.	[37]
Etoposide	DMNH3PG	Approved	PRA1 family protein 3 (ARL6IP5) increases the response to substance of Etoposide.	[38]

26 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 PRA1 family protein 3 (ARL6IP5).	[16]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of PRA1 family protein 3 (ARL6IP5).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of PRA1 family protein 3 (ARL6IP5).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of PRA1 family protein 3 (ARL6IP5).	[19]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of PRA1 family protein 3 (ARL6IP5).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of PRA1 family protein 3 (ARL6IP5).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of PRA1 family protein 3 (ARL6IP5).	[22]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of PRA1 family protein 3 (ARL6IP5).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of PRA1 family protein 3 (ARL6IP5).	[24]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of PRA1 family protein 3 (ARL6IP5).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of PRA1 family protein 3 (ARL6IP5).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of PRA1 family protein 3 (ARL6IP5).	[22]
Marinol	DM70IK5	Approved	Marinol increases the expression of PRA1 family protein 3 (ARL6IP5).	[27]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of PRA1 family protein 3 (ARL6IP5).	[20]
Aspirin	DM672AH	Approved	Aspirin increases the expression of PRA1 family protein 3 (ARL6IP5).	[28]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of PRA1 family protein 3 (ARL6IP5).	[29]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of PRA1 family protein 3 (ARL6IP5).	[30]
Fenretinide	DMRD5SP	Phase 3	Fenretinide affects the expression of PRA1 family protein 3 (ARL6IP5).	[31]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of PRA1 family protein 3 (ARL6IP5).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of PRA1 family protein 3 (ARL6IP5).	[32]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of PRA1 family protein 3 (ARL6IP5).	[33]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of PRA1 family protein 3 (ARL6IP5).	[34]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of PRA1 family protein 3 (ARL6IP5).	[35]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of PRA1 family protein 3 (ARL6IP5).	[36]
AHPN	DM8G6O4	Investigative	AHPN affects the expression of PRA1 family protein 3 (ARL6IP5).	[31]
Protoporphyrin IX	DMWYE7A	Investigative	Protoporphyrin IX increases the expression of PRA1 family protein 3 (ARL6IP5).	[20]

References

• [1] JWA suppresses the invasion of human breast carcinoma cells by downregulating the expression of CXCR4.Mol Med Rep. 2018 Jun;17(6):8137-8144. doi: 10.3892/mmr.2018.8866. Epub 2018 Apr 11.
• [2] Identification and functional characterization of JWA polymorphisms and their association with risk of gastric cancer and esophageal squamous cell carcinoma in a Chinese population.J Toxicol Environ Health A. 2007 Jun;70(11):885-94. doi: 10.1080/15287390701285915.
• [3] RNF185 modulates JWA ubiquitination and promotes gastric cancer metastasis.Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1552-1561. doi: 10.1016/j.bbadis.2018.02.013. Epub 2018 Feb 23.
• [4] Single nucleotide polymorphism of the JWA gene is associated with risk of leukemia: a case-control study in a Chinese population.J Toxicol Environ Health A. 2007 Jun;70(11):895-900. doi: 10.1080/15287390701285956.
• [5] Emerging JWA-targeted Pt(IV) prodrugs conjugated with CX-4945 to overcome chemo-immune-resistance.Biochem Biophys Res Commun. 2020 Jan 15;521(3):753-761. doi: 10.1016/j.bbrc.2019.10.184. Epub 2019 Nov 6.
• [6] Effects of JWA, XRCC1 and BRCA1 mRNA expression on molecular staging for personalized therapy in patients with advanced esophageal squamous cell carcinoma.BMC Cancer. 2015 Apr 30;15:331. doi: 10.1186/s12885-015-1364-0.
• [7] Prognostic and predictive role of JWA and XRCC1 expressions in gastric cancer.Clin Cancer Res. 2012 May 15;18(10):2987-96. doi: 10.1158/1078-0432.CCR-11-2863. Epub 2012 Mar 27.
• [8] Effects of haptoglobin polymorphisms and deficiency on susceptibility to inflammatory bowel disease and on severity of murine colitis.Gut. 2012 Apr;61(4):528-34. doi: 10.1136/gut.2011.240978. Epub 2011 Jun 27.
• [9] JWA suppresses tumor angiogenesis via Sp1-activated matrix metalloproteinase-2 and its prognostic significance in human gastric cancer.Carcinogenesis. 2014 Feb;35(2):442-51. doi: 10.1093/carcin/bgt311. Epub 2013 Sep 26.
• [10] GTRAP3-18 regulates food intake and body weight by interacting with pro-opiomelanocortin.FASEB J. 2018 Jan;32(1):330-341. doi: 10.1096/fj.201700421R. Epub 2017 Sep 13.
• [11] Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice.Cell Death Dis. 2018 Mar 2;9(3):352. doi: 10.1038/s41419-018-0381-8.
• [12] Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia.Schizophr Res. 2008 Sep;104(1-3):108-20. doi: 10.1016/j.schres.2008.06.012. Epub 2008 Aug 3.
• [13] JWA regulates chronic morphine dependence via the delta opioid receptor.Biochem Biophys Res Commun. 2011 Jun 10;409(3):520-5. doi: 10.1016/j.bbrc.2011.05.037. Epub 2011 May 11.
• [14] Haptoglobin genotype, anaemia and malaria in Gambian children.Trop Med Int Health. 2008 Jan;13(1):76-82. doi: 10.1111/j.1365-3156.2007.01976.x.
• [15] Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer.Gut. 2004 Apr;53(4):573-80. doi: 10.1136/gut.2003.030841.
• [16] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [17] 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.
• [18] JWA, a novel signaling molecule, involved in all-trans retinoic acid induced differentiation of HL-60 cells. J Biomed Sci. 2006 May;13(3):357-71. doi: 10.1007/s11373-005-9068-0. Epub 2006 Feb 9.
• [19] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [20] JWA, a novel signaling molecule, involved in the induction of differentiation of human myeloid leukemia cells. Biochem Biophys Res Commun. 2006 Mar 10;341(2):440-50. doi: 10.1016/j.bbrc.2005.12.197. Epub 2006 Jan 11.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [28] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [29] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [30] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [31] Comparing the effect of ATRA, 4-HPR, and CD437 in bladder cancer cells. Front Biosci. 2006 Sep 1;11:2007-16. doi: 10.2741/1942.
• [32] Proteomics and disease network associations evaluation of environmentally relevant Bisphenol A concentrations in a human 3D neural stem cell model. Front Cell Dev Biol. 2023 Aug 16;11:1236243. doi: 10.3389/fcell.2023.1236243. eCollection 2023.
• [33] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [34] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [35] JWA antagonizes paraquat-induced neurotoxicity via activation of Nrf2. Toxicol Lett. 2017 Aug 5;277:32-40. doi: 10.1016/j.toxlet.2017.04.011. Epub 2017 Apr 18.
• [36] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [37] JWA is required for arsenic trioxide induced apoptosis in HeLa and MCF-7 cells via reactive oxygen species and mitochondria linked signal pathway. Toxicol Appl Pharmacol. 2008 Jul 1;230(1):33-40. doi: 10.1016/j.taap.2008.01.041. Epub 2008 Feb 20.
• [38] JWA sensitizes P-glycoprotein-mediated drug-resistant choriocarcinoma cells to etoposide via JNK and mitochondrial-associated signal pathway. J Toxicol Environ Health A. 2009;72(11-12):774-81. doi: 10.1080/15287390902841649.