Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ0QR5L)

• DOT Name: Flotillin-2 (FLOT2)
• Synonyms: Epidermal surface antigen; ESA; Membrane component chromosome 17 surface marker 1
• Gene Name: FLOT2
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Advanced cancer
  Anemia
  Atrial fibrillation
  Bacillary dysentery
  Breast neoplasm
  Carcinoma
  Estrogen-receptor positive breast cancer
  Gastric cancer
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Melanoma
  Nasopharyngeal carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic adenocarcinoma
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Substance abuse
  Chronic renal failure
  End-stage renal disease
  Lung adenocarcinoma
  Chronic kidney disease
  Coronary atherosclerosis
  Coronary heart disease
  Ductal breast carcinoma in situ
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Small-cell lung cancer
  Venous thromboembolism
• UniProt ID: FLOT2_HUMAN
• Pfam ID: PF01145
• Sequence:
  MGNCHTVGPNEALVVSGGCCGSDYKQYVFGGWAWAWWCISDTQRISLEIMTLQPRCEDVE
  TAEGVALTVTGVAQVKIMTEKELLAVACEQFLGKNVQDIKNVVLQTLEGHLRSILGTLTV
  EQIYQDRDQFAKLVREVAAPDVGRMGIEILSFTIKDVYDKVDYLSSLGKTQTAVVQRDAD
  IGVAEAERDAGIREAECKKEMLDVKFMADTKIADSKRAFELQKSAFSEEVNIKTAEAQLA
  YELQGAREQQKIRQEEIEIEVVQRKKQIAVEAQEILRTDKELIATVRRPAEAEAHRIQQI
  AEGEKVKQVLLAQAEAEKIRKIGEAEAAVIEAMGKAEAERMKLKAEAYQKYGDAAKMALV
  LEALPQIAAKIAAPLTKVDEIVVLSGDNSKVTSEVNRLLAELPASVHALTGVDLSKIPLI
  KKATGVQV
• Function: May act as a scaffolding protein within caveolar membranes, functionally participating in formation of caveolae or caveolae-like vesicles. May be involved in epidermal cell adhesion and epidermal structure and function.
• Tissue Specificity: In skin, expressed in epidermis and epidermal appendages but not in dermis. Expressed in all layers of the epidermis except the basal layer. In hair follicles, expressed in the suprabasal layer but not the basal layer. Also expressed in melanoma and carcinoma cell lines, fibroblasts and foreskin melanocytes.
• KEGG Pathway: Insulin sig.ling pathway (hsa04910)
• Reactome Pathway:
  Regulation of necroptotic cell death (R-HSA-5675482)
  Synaptic adhesion-like molecules (R-HSA-8849932)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  RND3 GTPase cycle (R-HSA-9696264)
  RND1 GTPase cycle (R-HSA-9696273)
  RIPK1-mediated regulated necrosis (R-HSA-5213460)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anemia	DISTVL0C	Strong	Biomarker	[3]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[4]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Carcinoma	DISH9F1N	Strong	Altered Expression	[7]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Biomarker	[8]
Gastric cancer	DISXGOUK	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Lung cancer	DISCM4YA	Strong	Altered Expression	[13]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[13]
Melanoma	DIS1RRCY	Strong	Altered Expression	[2]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[13]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[9]
Substance abuse	DIS327VW	Strong	Biomarker	[17]
Chronic renal failure	DISGG7K6	moderate	Biomarker	[18]
End-stage renal disease	DISXA7GG	moderate	Biomarker	[18]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[19]
Chronic kidney disease	DISW82R7	Limited	Altered Expression	[20]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[21]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[21]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Biomarker	[22]
Matthew-Wood syndrome	DISA7HR7	Limited	Biomarker	[23]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[23]
Small-cell lung cancer	DISK3LZD	Limited	Altered Expression	[24]
Venous thromboembolism	DISUR7CR	Limited	Genetic Variation	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Flotillin-2 (FLOT2).	[26]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Flotillin-2 (FLOT2).	[27]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Flotillin-2 (FLOT2).	[28]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Flotillin-2 (FLOT2).	[29]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Flotillin-2 (FLOT2).	[30]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Flotillin-2 (FLOT2).	[31]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Flotillin-2 (FLOT2).	[32]
Selenium	DM25CGV	Approved	Selenium increases the expression of Flotillin-2 (FLOT2).	[33]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Flotillin-2 (FLOT2).	[34]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Flotillin-2 (FLOT2).	[35]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Flotillin-2 (FLOT2).	[36]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Flotillin-2 (FLOT2).	[36]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Flotillin-2 (FLOT2).	[37]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Flotillin-2 (FLOT2).	[38]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Flotillin-2 (FLOT2).	[39]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Flotillin-2 (FLOT2).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Flotillin-2 (FLOT2).	[42]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Flotillin-2 (FLOT2).	[43]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Flotillin-2 (FLOT2).	[40]

References

• [1] The study of mechanism of miR-34c-5p targeting FLOT2 to regulate proliferation, migration and invasion of osteosarcoma cells.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):3559-3568. doi: 10.1080/21691401.2019.1640714.
• [2] FLOT2 overexpression is associated with the progression and prognosis of human colorectal cancer.Oncol Lett. 2019 Mar;17(3):2802-2808. doi: 10.3892/ol.2019.9882. Epub 2019 Jan 2.
• [3] Trends in anemia care in non-dialysis-dependent chronic kidney disease (CKD) patients in the United States (2006-2015).BMC Nephrol. 2018 Nov 9;19(1):318. doi: 10.1186/s12882-018-1119-7.
• [4] STAR mapping method to identify driving sites in persistent atrial fibrillation: Application through sequential mapping.J Cardiovasc Electrophysiol. 2019 Dec;30(12):2694-2703. doi: 10.1111/jce.14201. Epub 2019 Oct 3.
• [5] Full genome sequence of a polyvalent bacteriophage infecting strains of Shigella, Salmonella, and Escherichia.Arch Virol. 2018 Nov;163(11):3207-3210. doi: 10.1007/s00705-018-3971-y. Epub 2018 Jul 28.
• [6] Increase in fatty acids and flotillins upon resveratrol treatment of human breast cancer cells.Sci Rep. 2019 Sep 27;9(1):13960. doi: 10.1038/s41598-019-50416-5.
• [7] SiRNA-mediated flotillin-2 (Flot2) downregulation inhibits cell proliferation, migration, and invasion in gastric carcinoma cells.Oncol Res. 2014;21(5):271-9. doi: 10.3727/096504014X13946737557031.
• [8] Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase.Breast Cancer Res Treat. 2011 Nov;130(2):387-98. doi: 10.1007/s10549-010-1300-6. Epub 2010 Dec 29.
• [9] miR-449a targets Flot2 and inhibits gastric cancer invasion by inhibiting TGF--mediated EMT.Diagn Pathol. 2015 Nov 14;10:202. doi: 10.1186/s13000-015-0435-5.
• [10] Flot2 targeted by miR-449 acts as a prognostic biomarker in glioma.Artif Cells Nanomed Biotechnol. 2019 Dec;47(1):250-255. doi: 10.1080/21691401.2018.1549062.
• [11] Prediction of future metastasis and molecular characterization of head and neck squamous-cell carcinoma based on transcriptome and genome analysis by microarrays.Oncogene. 2008 Nov 20;27(51):6607-22. doi: 10.1038/onc.2008.251. Epub 2008 Aug 4.
• [12] Flot2 promotes tumor growth and metastasis through modulating cell cycle and inducing epithelial-mesenchymal transition of hepatocellular carcinoma.Am J Cancer Res. 2017 May 1;7(5):1068-1083. eCollection 2017.
• [13] Expression of flotillin-2 in human non-small cell lung cancer and its correlation with tumor progression and patient survival.Int J Clin Exp Pathol. 2015 Jan 1;8(1):601-7. eCollection 2015.
• [14] Prognostic value of flotillins (flotillin-1 and flotillin-2) in human cancers: A meta-analysis.Clin Chim Acta. 2018 Jun;481:90-98. doi: 10.1016/j.cca.2018.02.036. Epub 2018 Feb 28.
• [15] Expression of CD44, CD24 and ESA in pancreatic adenocarcinoma cell lines varies with local microenvironment.Hepatobiliary Pancreat Dis Int. 2011 Aug;10(4):428-34. doi: 10.1016/s1499-3872(11)60073-8.
• [16] microRNA-802 inhibits epithelial-mesenchymal transition through targeting flotillin-2 in human prostate cancer.Biosci Rep. 2017 Mar 15;37(2):BSR20160521. doi: 10.1042/BSR20160521. Print 2017 Apr 30.
• [17] Trends In Substance Use And Related Disorders: Analysis of the Epidemiological Survey of Substance Abuse 1995 to 2018.Dtsch Arztebl Int. 2019 Sep 2;116(35-36):585-591. doi: 10.3238/arztebl.2019.0585.
• [18] Personalized Anemia Management and Precision Medicine in ESA and Iron Pharmacology in End-Stage Kidney Disease.Semin Nephrol. 2018 Jul;38(4):410-417. doi: 10.1016/j.semnephrol.2018.05.010.
• [19] miR-133 involves in lung adenocarcinoma cell metastasis by targeting FLOT2.Artif Cells Nanomed Biotechnol. 2018 Mar;46(2):224-230. doi: 10.1080/21691401.2017.1324467. Epub 2017 May 14.
• [20] Effect of achieved hemoglobin level on renal outcome in non-dialysis chronic kidney disease (CKD) patients receiving epoetin beta pegol: MIRcerA CLinical Evidence on Renal Survival in CKD patients with renal anemia (MIRACLE-CKD Study).Clin Exp Nephrol. 2019 Mar;23(3):349-361. doi: 10.1007/s10157-018-1649-0. Epub 2018 Oct 5.
• [21] Flotillin-2 Gene Is Associated with Coronary Artery Disease in Chinese Han Population.Genet Test Mol Biomarkers. 2015 Dec;19(12):679-83. doi: 10.1089/gtmb.2015.0121. Epub 2015 Nov 10.
• [22] Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer.Oncogene. 2013 Oct 17;32(42):5111-22. doi: 10.1038/onc.2012.519. Epub 2012 Dec 3.
• [23] Membranous CD24 drives the epithelial phenotype of pancreatic cancer.Oncotarget. 2016 Aug 2;7(31):49156-49168. doi: 10.18632/oncotarget.9402.
• [24] MicroRNA-485-5p suppresses the proliferation, migration and invasion of small cell lung cancer cells by targeting flotillin-2.Bioengineered. 2019 Dec;10(1):1-12. doi: 10.1080/21655979.2019.1586056.
• [25] European guidelines on perioperative venous thromboembolism prophylaxis: Surgery in the elderly.Eur J Anaesthesiol. 2018 Feb;35(2):116-122. doi: 10.1097/EJA.0000000000000705.
• [26] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [27] 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.
• [28] 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.
• [29] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [30] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [31] 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.
• [32] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [33] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [34] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [35] 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.
• [36] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [37] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [38] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [39] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [40] 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.
• [41] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [42] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [43] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.