Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT77GBY8)

DOT Name	Aquaporin-5 (AQP5)
Synonyms	AQP-5
Gene Name	AQP5
Related Disease	Esophageal squamous cell carcinoma ( ) Nephropathy ( ) Non-insulin dependent diabetes ( ) Non-small-cell lung cancer ( ) Adult respiratory distress syndrome ( ) Advanced cancer ( ) B-cell neoplasm ( ) Carcinoma ( ) Chronic obstructive pulmonary disease ( ) Colon cancer ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Dental caries ( ) Diabetic kidney disease ( ) Diffuse nonepidermolytic palmoplantar keratoderma ( ) Endometriosis ( ) Epithelial ovarian cancer ( ) Hepatocellular carcinoma ( ) Keratoconus ( ) Liver cancer ( ) Lung adenocarcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Lung squamous cell carcinoma ( ) Ovarian cancer ( ) Palmoplantar keratoderma, Bothnian type ( ) Pneumonia ( ) Pneumonitis ( ) Prostate cancer ( ) Prostate carcinoma ( ) Sjogren syndrome ( ) Squamous cell carcinoma ( ) Triple negative breast cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Chronic kidney disease ( ) Coronary atherosclerosis ( ) Coronary heart disease ( ) High blood pressure ( ) Inflammatory bowel disease ( ) Meningioma ( ) Metastatic malignant neoplasm ( ) Sarcoma ( ) Obsolete nonepidermolytic palmoplantar keratoderma ( ) Hyperglycemia ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Invasive ductal breast carcinoma ( ) Ovarian neoplasm ( ) Pancreatic ductal carcinoma ( )
UniProt ID	AQP5_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	3D9S; 5C5X; 5DYE; 7STC
Pfam ID	PF00230
Sequence	MKKEVCSVAFLKAVFAEFLATLIFVFFGLGSALKWPSALPTILQIALAFGLAIGTLAQAL GPVSGGHINPAITLALLVGNQISLLRAFFYVAAQLVGAIAGAGILYGVAPLNARGNLAVN ALNNNTTQGQAMVVELILTFQLALCIFASTDSRRTSPVGSPALSIGLSVTLGHLVGIYFT GCSMNPARSFGPAVVMNRFSPAHWVFWVGPIVGAVLAAILYFYLLFPNSLSLSERVAIIK GTYEPDEDWEEQREERKKTMELTTR
Function	Forms a water-specific channel. Plays an important role in fluid secretion in salivary glands. Required for TRPV4 activation by hypotonicity. Together with TRPV4, controls regulatory volume decrease in salivary epithelial cells. Seems to play a redundant role in water transport in the eye, lung and in sweat glands.
Tissue Specificity	Detected in skin eccrine sweat glands, at the apical cell membrane and at intercellular canaliculi (at protein level).
KEGG Pathway	Salivary secretion (hsa04970 )
Reactome Pathway	Passive transport by Aquaporins (R-HSA-432047 )

Molecular Interaction Atlas (MIA) of This DOT

49 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
Nephropathy	DISXWP4P	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Biomarker	[3]
Adult respiratory distress syndrome	DISIJV47	Strong	Altered Expression	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
B-cell neoplasm	DISVY326	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Altered Expression	[7]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Dental caries	DISRBCMD	Strong	Altered Expression	[11]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[12]
Diffuse nonepidermolytic palmoplantar keratoderma	DISKLJS3	Strong	GermlineCausalMutation	[13]
Endometriosis	DISX1AG8	Strong	Biomarker	[14]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[15]
Keratoconus	DISOONXH	Strong	Altered Expression	[16]
Liver cancer	DISDE4BI	Strong	Altered Expression	[17]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[18]
Lung cancer	DISCM4YA	Strong	Biomarker	[19]
Lung carcinoma	DISTR26C	Strong	Biomarker	[19]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[17]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[7]
Palmoplantar keratoderma, Bothnian type	DIS6PMZ6	Strong	Autosomal dominant	[20]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[4]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[4]
Prostate cancer	DISF190Y	Strong	Altered Expression	[21]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[21]
Sjogren syndrome	DISUBX7H	Strong	Altered Expression	[22]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[23]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[24]
Breast cancer	DIS7DPX1	moderate	Biomarker	[25]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[25]
Chronic kidney disease	DISW82R7	moderate	Biomarker	[26]
Coronary atherosclerosis	DISKNDYU	moderate	Altered Expression	[27]
Coronary heart disease	DIS5OIP1	moderate	Altered Expression	[27]
High blood pressure	DISY2OHH	moderate	Biomarker	[28]
Inflammatory bowel disease	DISGN23E	moderate	Altered Expression	[29]
Meningioma	DISPT4TG	moderate	Genetic Variation	[30]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[26]
Sarcoma	DISZDG3U	moderate	Biomarker	[31]
Obsolete nonepidermolytic palmoplantar keratoderma	DISX0KAS	Supportive	Autosomal dominant	[13]
Hyperglycemia	DIS0BZB5	Disputed	Biomarker	[32]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[33]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[34]
Ovarian neoplasm	DISEAFTY	Limited	Altered Expression	[35]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[36]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Aquaporin-5 (AQP5).	[37]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Aquaporin-5 (AQP5).	[44]
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8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Aquaporin-5 (AQP5).	[38]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Aquaporin-5 (AQP5).	[39]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Aquaporin-5 (AQP5).	[40]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Aquaporin-5 (AQP5).	[41]
Ergotidine	DM78IME	Approved	Ergotidine decreases the expression of Aquaporin-5 (AQP5).	[42]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Aquaporin-5 (AQP5).	[45]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Aquaporin-5 (AQP5).	[46]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the expression of Aquaporin-5 (AQP5).	[39]
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⏷ Show the Full List of 8 Drug(s)

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbachol	DMX9K8F	Approved	Carbachol affects the localization of Aquaporin-5 (AQP5).	[43]
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References

1	The expression and role of Aquaporin 5 in esophageal squamous cell carcinoma.J Gastroenterol. 2014 Apr;49(4):655-66. doi: 10.1007/s00535-013-0827-9. Epub 2013 May 9.
2	Urinary AQP5 is independently associated with eGFR decline in patients with type 2 diabetes and nephropathy.Diabetes Res Clin Pract. 2019 Sep;155:107805. doi: 10.1016/j.diabres.2019.107805. Epub 2019 Aug 1.
3	Expression of aquaporin 5 (AQP5) promotes tumor invasion in human non small cell lung cancer.PLoS One. 2008 May 14;3(5):e2162. doi: 10.1371/journal.pone.0002162.
4	Aquaporin 5 -1364A/C Promoter Polymorphism Is Associated with Pulmonary Inflammation and Survival in Acute Respiratory Distress Syndrome.Anesthesiology. 2019 Mar;130(3):404-413. doi: 10.1097/ALN.0000000000002560.
5	Aquaporins differentially regulate cell-cell adhesion in MDCK cells.FASEB J. 2019 Jun;33(6):6980-6994. doi: 10.1096/fj.201802068RR. Epub 2019 Mar 6.
6	Postnatal changes in the development of rat submandibular glands in offspring of diabetic mothers: Biochemical, histological and ultrastructural study.PLoS One. 2018 Oct 10;13(10):e0205372. doi: 10.1371/journal.pone.0205372. eCollection 2018.
7	Different Prognostic Implications of Aquaporin-1 and Aquaporin-5 Expression among Different Histological Types of Ovarian Carcinoma.Pathol Oncol Res. 2020 Jan;26(1):263-271. doi: 10.1007/s12253-018-0456-y. Epub 2018 Jul 19.
8	S-allylmercapto-l-cysteine modulates MUC5AC and AQP5 secretions in a COPD model via NF-B signaling pathway.Int Immunopharmacol. 2016 Oct;39:307-313. doi: 10.1016/j.intimp.2016.08.002. Epub 2016 Aug 9.
9	AQP5 silencing suppresses p38 MAPK signaling and improves drug resistance in colon cancer cells.Tumour Biol. 2014 Jul;35(7):7035-45. doi: 10.1007/s13277-014-1956-3. Epub 2014 Apr 23.
10	RNA interference-mediated silencing of aquaporin (AQP)-5 hinders angiogenesis of colorectal tumor by suppressing the production of vascular endothelial growth factor.Neoplasma. 2018;65(1):55-65. doi: 10.4149/neo_2018_161019N487.
11	Aquaporin 5 Interacts with Fluoride and Possibly Protects against Caries.PLoS One. 2015 Dec 2;10(12):e0143068. doi: 10.1371/journal.pone.0143068. eCollection 2015.
12	Urinary Excretion of Kidney Aquaporins as Possible Diagnostic Biomarker of Diabetic Nephropathy.J Diabetes Res. 2017;2017:4360357. doi: 10.1155/2017/4360357. Epub 2017 Jan 26.
13	Mutations in AQP5, encoding a water-channel protein, cause autosomal-dominant diffuse nonepidermolytic palmoplantar keratoderma. Am J Hum Genet. 2013 Aug 8;93(2):330-5. doi: 10.1016/j.ajhg.2013.06.008. Epub 2013 Jul 3.
14	Aquaporin 5 Plays a Role in Estrogen-Induced Ectopic Implantation of Endometrial Stromal Cells in Endometriosis.PLoS One. 2015 Dec 17;10(12):e0145290. doi: 10.1371/journal.pone.0145290. eCollection 2015.
15	MicroRNA-325-3p inhibits cell proliferation and induces apoptosis in hepatitis B virus-related hepatocellular carcinoma by down-regulation of aquaporin 5.Cell Mol Biol Lett. 2019 Feb 12;24:13. doi: 10.1186/s11658-019-0137-1. eCollection 2019.
16	Comparative expression analysis of aquaporin-5 (AQP5) in keratoconic and healthy corneas.Mol Vis. 2008 Apr 25;14:756-61.
17	Aquaporins 1, 3 and 5 in Different Tumors, their Expression, Prognosis Value and Role as New Therapeutic Targets.Pathol Oncol Res. 2020 Apr;26(2):615-625. doi: 10.1007/s12253-019-00646-9. Epub 2019 Mar 29.
18	Prognostic implication of aquaporin 1 overexpression in resected lung adenocarcinoma.Interact Cardiovasc Thorac Surg. 2017 Dec 1;25(6):856-861. doi: 10.1093/icvts/ivx202.
19	Silencing of aquaporin5 inhibits the growth of A549 lung cancer cells in vitro and in vivo.Int J Oncol. 2018 May;52(5):1643-1650. doi: 10.3892/ijo.2018.4326. Epub 2018 Mar 16.
20	The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
21	Aquaporin 5 expression is frequent in prostate cancer and shows a dichotomous correlation with tumor phenotype and PSA recurrence.Hum Pathol. 2016 Feb;48:102-10. doi: 10.1016/j.humpath.2015.09.026. Epub 2015 Oct 22.
22	Blockade of CD40-CD154 pathway interactions suppresses ectopic lymphoid structures and inhibits pathology in the NOD/ShiLtJ mouse model of Sjgren's syndrome.Ann Rheum Dis. 2019 Jul;78(7):974-978. doi: 10.1136/annrheumdis-2018-213929. Epub 2019 Mar 22.
23	AQP1, AQP5, Bcl-2 and p16 in pharyngeal squamous cell carcinoma.J Laryngol Otol. 2015 Jun;129(6):580-6. doi: 10.1017/S002221511500119X.
24	Expression of AQP3 and AQP5 as a prognostic marker in triple-negative breast cancer.Oncol Lett. 2018 Aug;16(2):2661-2667. doi: 10.3892/ol.2018.8955. Epub 2018 Jun 12.
25	Human Aquaporin-5 Facilitates Hydrogen Peroxide Permeation Affecting Adaption to Oxidative Stress and Cancer Cell Migration.Cancers (Basel). 2019 Jul 3;11(7):932. doi: 10.3390/cancers11070932.
26	AQP5 promotes hepatocellular carcinoma metastasis via NF-B-regulated epithelial-mesenchymal transition.Biochem Biophys Res Commun. 2017 Aug 19;490(2):343-348. doi: 10.1016/j.bbrc.2017.06.046. Epub 2017 Jun 12.
27	A novel-1364A/C aquaporin 5 gene promoter polymorphism influences the responses to salt loading of the renin-angiotensin-aldosterone system and of blood pressure in young healthy men.Basic Res Cardiol. 2008 Nov;103(6):598-610. doi: 10.1007/s00395-008-0750-z. Epub 2008 Oct 10.
28	Proteomic analysis reveals an impaired Ca(2+)/AQP5 pathway in the submandibular gland in hypertension.Sci Rep. 2017 Nov 6;7(1):14524. doi: 10.1038/s41598-017-15211-0.
29	Aquaporins in Digestive System.Adv Exp Med Biol. 2017;969:123-130. doi: 10.1007/978-94-024-1057-0_8.
30	Expression of aquaporin 5 and the AQP5 polymorphism A(-1364)C in association with peritumoral brain edema in meningioma patients.J Neurooncol. 2013 Apr;112(2):297-305. doi: 10.1007/s11060-013-1064-z. Epub 2013 Feb 8.
31	Aquaporin-1 and -5 are involved in the invasion and proliferation of soft tissue sarcomas.Pathol Res Pract. 2018 Jan;214(1):80-88. doi: 10.1016/j.prp.2017.11.006. Epub 2017 Nov 12.
32	Low-level laser therapy with 850nm recovers salivary function via membrane redistribution of aquaporin 5 by reducing intracellular Ca(2+) overload and ER stress during hyperglycemia.Biochim Biophys Acta Gen Subj. 2018 Aug;1862(8):1770-1780. doi: 10.1016/j.bbagen.2018.05.008. Epub 2018 May 9.
33	Heat shock exerts anticancer effects on liver cancer via autophagic degradation of aquaporin 5.Int J Oncol. 2017 May;50(5):1857-1867. doi: 10.3892/ijo.2017.3940. Epub 2017 Mar 29.
34	Immunohistochemical evalulation of activated Ras and Rac1 as potential downstream effectors of aquaporin-5 in breast cancer invivo.Biochem Biophys Res Commun. 2017 Nov 25;493(3):1210-1216. doi: 10.1016/j.bbrc.2017.09.125. Epub 2017 Sep 25.
35	Down-regulated aquaporin 5 inhibits proliferation and migration of human epithelial ovarian cancer 3AO cells.J Ovarian Res. 2014 Aug 15;7:78. doi: 10.1186/s13048-014-0078-2.
36	Differential expression of aquaporin-3 and aquaporin-5 in pancreatic ductal adenocarcinoma.J Surg Oncol. 2017 Jun;115(8):980-996. doi: 10.1002/jso.24605. Epub 2017 May 4.
37	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
38	Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
39	Cordycepin attenuates Salivary Hypofunction through the Prevention of Oxidative Stress in Human Submandibular Gland Cells. Int J Med Sci. 2020 Jul 6;17(12):1733-1743. doi: 10.7150/ijms.46707. eCollection 2020.
40	Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
41	Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
42	Glycyrrhizin attenuates histamine-mediated MUC5AC upregulation, inflammatory cytokine production, and aquaporin 5 downregulation through suppressing the NF-B pathway in human nasal epithelial cells. Chem Biol Interact. 2018 Apr 1;285:21-26. doi: 10.1016/j.cbi.2018.02.010. Epub 2018 Feb 13.
43	Histamine H1 receptor induces cytosolic calcium increase and aquaporin translocation in human salivary gland cells. J Pharmacol Exp Ther. 2009 Aug;330(2):403-12.
44	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.
45	Bisphenol A suppresses glucocorticoid target gene (ENaC) expression via a novel ER/NF-B/GR signalling pathway in lung epithelial cells. Arch Toxicol. 2017 Apr;91(4):1727-1737. doi: 10.1007/s00204-016-1807-7. Epub 2016 Aug 13.
46	Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.