Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9PPRHE)

• DOT Name: FXYD domain-containing ion transport regulator 3 (FXYD3)
• Synonyms: Chloride conductance inducer protein Mat-8; Mammary tumor 8 kDa protein; Phospholemman-like; Sodium/potassium-transporting ATPase subunit FXYD3
• Gene Name: FXYD3
• Related Disease:
  Advanced cancer
  Benign prostatic hyperplasia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Chronic pancreatitis
  Colorectal carcinoma
  Colorectal neoplasm
  Esophageal squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Pancreatic tumour
  Prostate adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Hepatocellular carcinoma
• UniProt ID: FXYD3_HUMAN
• Pfam ID: PF02038
• Sequence:
  MQKVTLGLLVFLAGFPVLDANDLEDKNSPFYYDWHSLQVGGLICAGVLCAMGIIIVMSAK
  CKCKFGQKSGHHPGETPPLITPGSAQS
• Function: Associates with and regulates the activity of the sodium/potassium-transporting ATPase (NKA) which transports Na(+) out of the cell and K(+) into the cell. Reduces glutathionylation of the NKA beta-1 subunit ATP1B1, thus reversing glutathionylation-mediated inhibition of ATP1B1. Induces a hyperpolarization-activated chloride current when expressed in Xenopus oocytes ; [Isoform 1]: Decreases the apparent K+ and Na+ affinity of the sodium/potassium-transporting ATPase over a large range of membrane potentials; [Isoform 2]: Decreases the apparent K+ affinity of the sodium/potassium-transporting ATPase only at slightly negative and positive membrane potentials and increases the apparent Na+ affinity over a large range of membrane potentials.
• Tissue Specificity: Isoform 1: Expressed mainly in differentiated cells (at protein level). Isoform 2: Expressed mainly in undifferentiated cells (at protein level).
• Reactome Pathway:
  Ion transport by P-type ATPases (R-HSA-936837)
  Potential therapeutics for SARS (R-HSA-9679191)
  Ion homeostasis (R-HSA-5578775)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Chronic pancreatitis	DISBUOMJ	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[8]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[9]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[6]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[10]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Altered Expression	[11]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[6]
Prostate adenocarcinoma	DISBZYU8	Strong	Biomarker	[12]
Prostate cancer	DISF190Y	Strong	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[5]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Disputed	Biomarker	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	FXYD domain-containing ion transport regulator 3 (FXYD3) increases the response to substance of Paclitaxel.	[25]

14 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 FXYD domain-containing ion transport regulator 3 (FXYD3).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[17]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[17]
Marinol	DM70IK5	Approved	Marinol decreases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[18]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[19]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[20]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[20]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[21]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[22]
Raltitrexed	DMT9K8G	Approved	Raltitrexed increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of FXYD domain-containing ion transport regulator 3 (FXYD3).	[13]

2 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 decreases the methylation of FXYD domain-containing ion transport regulator 3 (FXYD3).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of FXYD domain-containing ion transport regulator 3 (FXYD3).	[24]

References

• [1] Prognostic significance of sodium-potassium ATPase regulator, FXYD3, in human hepatocellular carcinoma.Oncol Lett. 2018 Mar;15(3):3024-3030. doi: 10.3892/ol.2017.7688. Epub 2017 Dec 21.
• [2] External validation of FXYD3 and KRT20 as predictive biomarkers for the presence of micrometastasis in muscle invasive bladder cancer lymph nodes.Actas Urol Esp. 2015 Oct;39(8):473-81. doi: 10.1016/j.acuro.2015.02.002. Epub 2015 Apr 25.
• [3] SOX9/FXYD3/Src Axis Is Critical for ER(+) Breast Cancer Stem Cell Function.Mol Cancer Res. 2019 Jan;17(1):238-249. doi: 10.1158/1541-7786.MCR-18-0610. Epub 2018 Sep 11.
• [4] Down-regulation of FXYD3 expression in human lung cancers: its mechanism and potential role in carcinogenesis.Am J Pathol. 2009 Dec;175(6):2646-56. doi: 10.2353/ajpath.2009.080571. Epub 2009 Nov 5.
• [5] Up-regulated expression of the MAT-8 gene in prostate cancer and its siRNA-mediated inhibition of expression induces a decrease in proliferation of human prostate carcinoma cells.Int J Oncol. 2004 Jan;24(1):97-105.
• [6] FXYD3 is overexpressed in pancreatic ductal adenocarcinoma and influences pancreatic cancer cell growth.Int J Cancer. 2006 Jan 1;118(1):43-54. doi: 10.1002/ijc.21257.
• [7] Expression of FXYD3 protein in relation to biological and clinicopathological variables in colorectal cancers.Chemotherapy. 2009;55(6):407-13. doi: 10.1159/000263227. Epub 2009 Dec 2.
• [8] Interaction of Mat-8 (FXYD-3) with Na+/K+-ATPase in colorectal cancer cells.Biol Pharm Bull. 2007 Apr;30(4):648-54. doi: 10.1248/bpb.30.648.
• [9] Overexpression of FXYD-3 is involved in the tumorigenesis and development of esophageal squamous cell carcinoma.Dis Markers. 2013;35(3):195-202. doi: 10.1155/2013/740201. Epub 2013 Aug 27.
• [10] Structural analysis of the cancer-specific promoter in mesothelin and in other genes overexpressed in cancers.J Biol Chem. 2011 Apr 8;286(14):11960-9. doi: 10.1074/jbc.M110.193458. Epub 2011 Feb 2.
• [11] Clinicopathological and prognostic significance of MUC13 and AGR2 expression in intraductal papillary mucinous neoplasms of the pancreas.Pancreatology. 2018 Jun;18(4):407-412. doi: 10.1016/j.pan.2018.04.003. Epub 2018 Apr 3.
• [12] Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer.Proc Natl Acad Sci U S A. 2018 May 8;115(19):E4473-E4482. doi: 10.1073/pnas.1802354115. Epub 2018 Apr 23.
• [13] 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.
• [14] Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [19] Progestins regulate genes that can elicit both proliferative and antiproliferative effects in breast cancer cells. Oncol Rep. 2008 Jun;19(6):1627-34.
• [20] 5-Fluorouracil: identification of novel downstream mediators of tumour response. Anticancer Res. 2004 Mar-Apr;24(2A):417-23.
• [21] 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.
• [22] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [23] 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.
• [24] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [25] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.