Details of Drug Off-Target (DOT)

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

• DOT Name: Bcl-2-related ovarian killer protein (BOK)
• Synonyms: hBOK; Bcl-2-like protein 9; Bcl2-L-9
• Gene Name: BOK
• Related Disease:
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Hydrocephalus
  Intestinal cancer
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
  Pre-eclampsia
  Transitional cell carcinoma
  Urothelial carcinoma
  Pancreatic cancer
  Gastric cancer
  Stomach cancer
• UniProt ID: BOK_HUMAN
• PDB ID: 6CKV
• Pfam ID: PF00452
• Sequence:
  MEVLRRSSVFAAEIMDAFDRSPTDKELVAQAKALGREYVHARLLRAGLSWSAPERAAPVP
  GRLAEVCAVLLRLGDELEMIRPSVYRNVARQLHISLQSEPVVTDAFLAVAGHIFSAGITW
  GKVVSLYAVAAGLAVDCVRQAQPAMVHALVDCLGEFVRKTLATWLRRRGGWTDVLKCVVS
  TDPGLRSHWLVAALCSFGRFLKAAFFVLLPER
• Function: [Isoform 1]: Apoptosis regulator that functions through different apoptotic signaling pathways. Plays a roles as pro-apoptotic protein that positively regulates intrinsic apoptotic process in a BAX- and BAK1-dependent manner or in a BAX- and BAK1-independent manner. In response to endoplasmic reticulum stress promotes mitochondrial apoptosis through downstream BAX/BAK1 activation and positive regulation of PERK-mediated unfolded protein response. Activates apoptosis independently of heterodimerization with survival-promoting BCL2 and BCL2L1 through induction of mitochondrial outer membrane permeabilization, in a BAX- and BAK1-independent manner, in response to inhibition of ERAD-proteasome degradation system, resulting in cytochrome c release. In response to DNA damage, mediates intrinsic apoptotic process in a TP53-dependent manner. Plays a role in granulosa cell apoptosis by CASP3 activation. Plays a roles as anti-apoptotic protein during neuronal apoptotic process, by negatively regulating poly ADP-ribose polymerase-dependent cell death through regulation of neuronal calcium homeostasis and mitochondrial bioenergetics in response to NMDA excitation. In addition to its role in apoptosis, may regulate trophoblast cell proliferation during the early stages of placental development, by acting on G1/S transition through regulation of CCNE1 expression. May also play a role as an inducer of autophagy by disrupting interaction between MCL1 and BECN1 ; [Isoform 2]: Pro-apoptotic molecule exerting its function through the mitochondrial pathway.
• Tissue Specificity: Expressed mainly in oocytes; weak expression in granulosa cells of the developing follicles. In adult human ovaries, expressed in granulosa cells at all follicular stages, but expression in primordial/primary follicles granulosa cell is stronger than in secondary and antral follicles.
• KEGG Pathway: Apoptosis - multiple species (hsa04215)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[4]
Intestinal cancer	DISYCNF1	Strong	Altered Expression	[5]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[6]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[6]
Pre-eclampsia	DISY7Q29	Strong	Biomarker	[7]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[8]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[8]
Pancreatic cancer	DISJC981	moderate	Biomarker	[9]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[10]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[10]

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 Bcl-2-related ovarian killer protein (BOK).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Bcl-2-related ovarian killer protein (BOK).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Bcl-2-related ovarian killer protein (BOK).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Bcl-2-related ovarian killer protein (BOK).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Bcl-2-related ovarian killer protein (BOK).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Bcl-2-related ovarian killer protein (BOK).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bcl-2-related ovarian killer protein (BOK).	[15]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Bcl-2-related ovarian killer protein (BOK).	[16]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Bcl-2-related ovarian killer protein (BOK).	[17]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Bcl-2-related ovarian killer protein (BOK).	[18]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Bcl-2-related ovarian killer protein (BOK).	[19]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Bcl-2-related ovarian killer protein (BOK).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Bcl-2-related ovarian killer protein (BOK).	[21]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Bcl-2-related ovarian killer protein (BOK).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Bcl-2-related ovarian killer protein (BOK).	[25]

References

• [1] Expression and Critical Role of Interleukin Enhancer Binding Factor 2 in Hepatocellular Carcinoma.Int J Mol Sci. 2016 Aug 22;17(8):1373. doi: 10.3390/ijms17081373.
• [2] Novel post-transcriptional and post-translational regulation of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 determine the fate of breast cancer cells to survive or die.Oncotarget. 2017 Sep 12;8(49):85984-85996. doi: 10.18632/oncotarget.20841. eCollection 2017 Oct 17.
• [3] The BAX/BAK-like protein BOK is a prognostic marker in colorectal cancer.Cell Death Dis. 2018 Jan 26;9(2):125. doi: 10.1038/s41419-017-0140-2.
• [4] Differential expression of stress response genes in the H-Tx rat model of congenital hydrocephalus.Brain Res Mol Brain Res. 2005 Aug 18;138(2):273-90. doi: 10.1016/j.molbrainres.2005.05.002.
• [5] WNT signaling controls expression of pro-apoptotic BOK and BAX in intestinal cancer.Biochem Biophys Res Commun. 2011 Mar 4;406(1):1-6. doi: 10.1016/j.bbrc.2010.12.070. Epub 2010 Dec 22.
• [6] BOK displays cell death-independent tumor suppressor activity in non-small-cell lung carcinoma.Int J Cancer. 2017 Nov 15;141(10):2050-2061. doi: 10.1002/ijc.30906. Epub 2017 Aug 7.
• [7] A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia.Cell Death Differ. 2005 May;12(5):441-52. doi: 10.1038/sj.cdd.4401593.
• [8] Integrated genomic and transcriptional analysis of the in vitro evolution of telomerase-immortalized urothelial cells (TERT-NHUC).Genes Chromosomes Cancer. 2009 Aug;48(8):694-710. doi: 10.1002/gcc.20672.
• [9] MicroRNA-296-5p Promotes Cell Invasion and Drug Resistance by Targeting Bcl2-Related Ovarian Killer, Leading to a Poor Prognosis in Pancreatic Cancer.Digestion. 2020;101(6):794-806. doi: 10.1159/000503225. Epub 2019 Sep 27.
• [10] Avicularin reversed multidrug-resistance in human gastric cancer through enhancing Bax and BOK expressions.Biomed Pharmacother. 2018 Jul;103:67-74. doi: 10.1016/j.biopha.2018.03.110. Epub 2018 Apr 7.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Pattern of expression of apoptosis and inflammatory genes in humans exposed to arsenic and/or fluoride. Sci Total Environ. 2010 Jan 15;408(4):760-7. doi: 10.1016/j.scitotenv.2009.11.016. Epub 2009 Dec 4.
• [17] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] 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.
• [20] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [25] 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.