Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6QINVO)

• DOT Name: Protein lifeguard 2 (FAIM2)
• Synonyms: Fas apoptotic inhibitory molecule 2; Neural membrane protein 35; Transmembrane BAX inhibitor motif-containing protein 2
• Gene Name: FAIM2
• Related Disease:
  Parkinson disease
  B-cell neoplasm
  Cholelithiasis
  Chronic obstructive pulmonary disease
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Hyperinsulinemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Myocardial infarction
  Neoplasm
  Niemann-Pick disease, type C1
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  High blood pressure
  Asthma
  Neuroblastoma
  Obesity
• UniProt ID: LFG2_HUMAN
• Pfam ID: PF01027
• Sequence:
  MTQGKLSVANKAPGTEGQQQVHGEKKEAPAVPSAPPSYEEATSGEGMKAGAFPPAPTAVP
  LHPSWAYVDPSSSSSYDNGFPTGDHELFTTFSWDDQKVRRVFVRKVYTILLIQLLVTLAV
  VALFTFCDPVKDYVQANPGWYWASYAVFFATYLTLACCSGPRRHFPWNLILLTVFTLSMA
  YLTGMLSSYYNTTSVLLCLGITALVCLSVTVFSFQTKFDFTSCQGVLFVLLMTLFFSGLI
  LAILLPFQYVPWLHAVYAALGAGVFTLFLALDTQLLMGNRRHSLSPEEYIFGALNIYLDI
  IYIFTFFLQLFGTNRE
• Function: Antiapoptotic protein which protects cells uniquely from Fas-induced apoptosis. Regulates Fas-mediated apoptosis in neurons by interfering with caspase-8 activation. May play a role in cerebellar development by affecting cerebellar size, internal granular layer (IGL) thickness, and Purkinje cell (PC) development.
• Tissue Specificity: Highly expressed in breast carcinoma tissues. Enhanced expression correlates with the grade of the tumor (grade II/grade III) in primary breast tumors (at protein level). Widely expressed. Expressed at high levels in the brain especially in the hippocampus.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Definitive	Biomarker	[1]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[2]
Cholelithiasis	DISERLZB	Strong	Genetic Variation	[3]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Hyperinsulinemia	DISIDWT6	Strong	Genetic Variation	[6]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[9]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Niemann-Pick disease, type C1	DIS9HUE3	Strong	Biomarker	[11]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[8]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[2]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[12]
Asthma	DISW9QNS	Limited	Biomarker	[13]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[14]
Obesity	DIS47Y1K	Limited	Genetic Variation	[15]

3 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 Protein lifeguard 2 (FAIM2).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Protein lifeguard 2 (FAIM2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein lifeguard 2 (FAIM2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein lifeguard 2 (FAIM2).	[17]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Protein lifeguard 2 (FAIM2).	[19]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of Protein lifeguard 2 (FAIM2).	[20]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Protein lifeguard 2 (FAIM2).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein lifeguard 2 (FAIM2).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein lifeguard 2 (FAIM2).	[23]
4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol	DMTMLXU	Investigative	4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol decreases the expression of Protein lifeguard 2 (FAIM2).	[17]

References

• [1] Faim2 contributes to neuroprotection by erythropoietin in transient brain ischemia.J Neurochem. 2018 May;145(3):258-270. doi: 10.1111/jnc.14296. Epub 2018 Feb 20.
• [2] LFG-500, a newly synthesized flavonoid, induces apoptosis in human ovarian carcinoma SKOV3 cells with involvement of the reactive oxygen species-mitochondria pathway.Exp Ther Med. 2017 Jun;13(6):2819-2827. doi: 10.3892/etm.2017.4343. Epub 2017 Apr 18.
• [3] Metabolic biomarkers and gallstone disease - a population-based study.Scand J Gastroenterol. 2017 Nov;52(11):1270-1277. doi: 10.1080/00365521.2017.1365166. Epub 2017 Aug 11.
• [4] MiR-3202 protects smokers from chronic obstructive pulmonary disease through inhibiting FAIM2: An in vivo and in vitro study.Exp Cell Res. 2018 Jan 15;362(2):370-377. doi: 10.1016/j.yexcr.2017.11.038. Epub 2017 Dec 5.
• [5] LncRNA DCST1-AS1 functions as a competing endogenous RNA to regulate FAIM2 expression by sponging miR-1254 in hepatocellular carcinoma.Clin Sci (Lond). 2019 Jan 30;133(2):367-379. doi: 10.1042/CS20180814. Print 2019 Jan 31.
• [6] Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population.Int J Obes (Lond). 2013 Jul;37(7):980-5. doi: 10.1038/ijo.2012.175. Epub 2012 Oct 23.
• [7] LFG-500, a novel synthetic flavonoid, suppresses epithelial-mesenchymal transition in human lung adenocarcinoma cells by inhibiting NLRP3 in inflammatory microenvironment.Cancer Lett. 2017 Aug 1;400:137-148. doi: 10.1016/j.canlet.2017.04.035. Epub 2017 Apr 29.
• [8] miR-193b availability is antagonized by LncRNA-SNHG7 for FAIM2-induced tumour progression in non-small cell lung cancer.Cell Prolif. 2018 Feb;51(1):e12406. doi: 10.1111/cpr.12406. Epub 2017 Nov 12.
• [9] LFG-500 inhibits the invasion of cancer cells via down-regulation of PI3K/AKT/NF-B signaling pathway.PLoS One. 2014 Mar 11;9(3):e91332. doi: 10.1371/journal.pone.0091332. eCollection 2014.
• [10] Novel association of the obesity risk-allele near Fas Apoptotic Inhibitory Molecule 2 (FAIM2) gene with heart rate and study of its effects on myocardial infarction in diabetic participants of the PREDIMED trial.Cardiovasc Diabetol. 2014 Jan 6;13:5. doi: 10.1186/1475-2840-13-5.
• [11] Association between obesity and polymorphisms in SEC16B, TMEM18, GNPDA2, BDNF, FAIM2 and MC4R in a Japanese population.J Hum Genet. 2009 Dec;54(12):727-31. doi: 10.1038/jhg.2009.106. Epub 2009 Oct 23.
• [12] Associations of obesity susceptibility loci with hypertension in Chinese children.Int J Obes (Lond). 2013 Jul;37(7):926-30. doi: 10.1038/ijo.2013.37. Epub 2013 Apr 16.
• [13] Analyses of shared genetic factors between asthma and obesity in children.J Allergy Clin Immunol. 2010 Sep;126(3):631-7.e1-8. doi: 10.1016/j.jaci.2010.06.030.
• [14] MYCN repression of Lifeguard/FAIM2 enhances neuroblastoma aggressiveness.Cell Death Dis. 2014 Sep 4;5(9):e1401. doi: 10.1038/cddis.2014.356.
• [15] The Expression of Aldolase B in Islets Is Negatively Associated With Insulin Secretion in Humans.J Clin Endocrinol Metab. 2018 Dec 1;103(12):4373-4383. doi: 10.1210/jc.2018-00791.
• [16] 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.
• [17] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [18] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [19] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [20] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [21] 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.
• [22] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.