Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0JPPJZ)

• DOT Name: Flotillin-1 (FLOT1)
• Gene Name: FLOT1
• Related Disease:
  Bladder transitional cell carcinoma
  Non-insulin dependent diabetes
  Tarsal-carpal coalition syndrome
  Transitional cell carcinoma
  Advanced cancer
  Aerodigestive tract cancer
  Benign neoplasm
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Metastatic prostate carcinoma
  Multiple sclerosis
  Nasopharyngeal carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pulmonary disease
  Schizophrenia
  Small-cell lung cancer
  Type-1 diabetes
  Breast neoplasm
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Lung cancer
  Major depressive disorder
  Neuroblastoma
  OPTN-related open angle glaucoma
  Q fever
• UniProt ID: FLOT1_HUMAN
• Pfam ID: PF01145
• Sequence:
  MFFTCGPNEAMVVSGFCRSPPVMVAGGRVFVLPCIQQIQRISLNTLTLNVKSEKVYTRHG
  VPISVTGIAQVKIQGQNKEMLAAACQMFLGKTEAEIAHIALETLEGHQRAIMAHMTVEEI
  YKDRQKFSEQVFKVASSDLVNMGISVVSYTLKDIHDDQDYLHSLGKARTAQVQKDARIGE
  AEAKRDAGIREAKAKQEKVSAQYLSEIEMAKAQRDYELKKAAYDIEVNTRRAQADLAYQL
  QVAKTKQQIEEQRVQVQVVERAQQVAVQEQEIARREKELEARVRKPAEAERYKLERLAEA
  EKSQLIMQAEAEAASVRMRGEAEAFAIGARARAEAEQMAKKAEAFQLYQEAAQLDMLLEK
  LPQVAEEISGPLTSANKITLVSSGSGTMGAAKVTGEVLDILTRLPESVERLTGVSISQVN
  HKPLRTA
• Function: May act as a scaffolding protein within caveolar membranes, functionally participating in formation of caveolae or caveolae-like vesicles.
• 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)
  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
Bladder transitional cell carcinoma	DISNL46A	Definitive	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[2]
Tarsal-carpal coalition syndrome	DISY90L2	Definitive	Altered Expression	[1]
Transitional cell carcinoma	DISWVVDR	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Aerodigestive tract cancer	DIS3AOQ7	Strong	Biomarker	[4]
Benign neoplasm	DISDUXAD	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[8]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[9]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[10]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Pulmonary disease	DIS6060I	Strong	Altered Expression	[13]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[14]
Small-cell lung cancer	DISK3LZD	Strong	Altered Expression	[13]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[15]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[16]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[11]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[17]
Major depressive disorder	DIS4CL3X	Limited	Altered Expression	[18]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[19]
OPTN-related open angle glaucoma	DISDR98A	Limited	Biomarker	[20]
Q fever	DISK1S90	Limited	Biomarker	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Carbamazepine	DMZOLBI	Approved	Flotillin-1 (FLOT1) increases the Stevens-Johnson syndrome ADR of Carbamazepine.	[36]

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 Flotillin-1 (FLOT1).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Flotillin-1 (FLOT1).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Flotillin-1 (FLOT1).	[24]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Flotillin-1 (FLOT1).	[25]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Flotillin-1 (FLOT1).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Flotillin-1 (FLOT1).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Flotillin-1 (FLOT1).	[28]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Flotillin-1 (FLOT1).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Flotillin-1 (FLOT1).	[30]
Selenium	DM25CGV	Approved	Selenium increases the expression of Flotillin-1 (FLOT1).	[31]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Flotillin-1 (FLOT1).	[32]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Flotillin-1 (FLOT1).	[24]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Flotillin-1 (FLOT1).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Flotillin-1 (FLOT1).	[34]

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 affects the methylation of Flotillin-1 (FLOT1).	[33]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Flotillin-1 (FLOT1).	[35]

References

• [1] Overexpression of flotillin-1 is involved in proliferation and recurrence of bladder transitional cell carcinoma.Oncol Rep. 2014 Aug;32(2):748-54. doi: 10.3892/or.2014.3221. Epub 2014 May 29.
• [2] Suppression of Hepatic FLOT1 (Flotillin-1) by Type 2 Diabetes Mellitus Impairs the Disposal of Remnant Lipoproteins via Syndecan-1.Arterioscler Thromb Vasc Biol. 2018 Jan;38(1):102-113. doi: 10.1161/ATVBAHA.117.310358. Epub 2017 Nov 21.
• [3] Clinical significance and comparison of flotillin 1 expression in left and right colon cancer.Oncol Lett. 2019 Aug;18(2):997-1004. doi: 10.3892/ol.2019.10401. Epub 2019 May 27.
• [4] 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.
• [5] Flotillin 1 is differentially expressed in human epithelial ovarian tumors.Neoplasma. 2018;65(4):561-571. doi: 10.4149/neo_2018_170714N483.
• [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] miRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1.Oncotarget. 2015 May 20;6(14):12543-57. doi: 10.18632/oncotarget.3815.
• [8] Flotillin-1 protein is upregulated in human endometrial cancer and localization shifts from epithelial to stromal with increasing tumor grade.Cancer Invest. 2016;34(1):26-31. doi: 10.3109/07357907.2015.1084313. Epub 2015 Dec 18.
• [9] Sumoylation of Flotillin-1 promotes EMT in metastatic prostate cancer by suppressing Snail degradation.Oncogene. 2019 Apr;38(17):3248-3260. doi: 10.1038/s41388-018-0641-1. Epub 2019 Jan 10.
• [10] Identification of the flotillin-1/2 heterocomplex as a target of autoantibodies in bona fide multiple sclerosis.J Neuroinflammation. 2017 Jun 23;14(1):123. doi: 10.1186/s12974-017-0900-z.
• [11] FLOT1 promotes tumor development, induces epithelial-mesenchymal transition, and modulates the cell cycle by regulating the Erk/Akt signaling pathway in lung adenocarcinoma.Thorac Cancer. 2019 Apr;10(4):909-917. doi: 10.1111/1759-7714.13027. Epub 2019 Mar 5.
• [12] 4.1N is involved in a flotillin-1/-catenin/Wnt pathway and suppresses cell proliferation and migration in non-small cell lung cancer cell lines.Tumour Biol. 2016 Sep;37(9):12713-12723. doi: 10.1007/s13277-016-5146-3. Epub 2016 Jul 22.
• [13] Flotillin1 promotes EMT of human small cell lung cancer via TGF- signaling pathway.Cancer Biol Med. 2018 Nov;15(4):400-414. doi: 10.20892/j.issn.2095-3941.2018.0053.
• [14] Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect.Schizophr Bull. 2019 Jun 18;45(4):824-834. doi: 10.1093/schbul/sby140.
• [15] A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.Nature. 2007 Aug 2;448(7153):591-4. doi: 10.1038/nature06010. Epub 2007 Jul 15.
• [16] MicroRNA-6809-5p mediates luteolin-induced anticancer effects against hepatoma by targeting flotillin 1.Phytomedicine. 2019 Apr;57:18-29. doi: 10.1016/j.phymed.2018.10.027. Epub 2018 Oct 22.
• [17] Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.Hum Mol Genet. 2012 Nov 15;21(22):4980-95. doi: 10.1093/hmg/dds334. Epub 2012 Aug 16.
• [18] Integration of GWAS and brain eQTL identifies FLOT1 as a risk gene for major depressive disorder.Neuropsychopharmacology. 2019 Aug;44(9):1542-1551. doi: 10.1038/s41386-019-0345-4. Epub 2019 Feb 16.
• [19] Flotillin-1 regulates oncogenic signaling in neuroblastoma cells by regulating ALK membrane association.Cancer Res. 2014 Jul 15;74(14):3790-801. doi: 10.1158/0008-5472.CAN-14-0241. Epub 2014 May 15.
• [20] Identification of flotillin-1 as a protein interacting with myocilin: implications for the pathogenesis of primary open-angle glaucoma.Biochem Biophys Res Commun. 2005 Nov 4;336(4):1201-6. doi: 10.1016/j.bbrc.2005.09.006.
• [21] Coxiella burnetii inhabits a cholesterol-rich vacuole and influences cellular cholesterol metabolism.Cell Microbiol. 2006 Mar;8(3):496-507. doi: 10.1111/j.1462-5822.2005.00641.x.
• [22] 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.
• [23] 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.
• [24] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [25] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [26] 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.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [33] 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.
• [34] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [35] 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.
• [36] Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004 Apr 1;428(6982):486. doi: 10.1038/428486a.