Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW29FB4)

• DOT Name: NADPH oxidase organizer 1 (NOXO1)
• Synonyms: NADPH oxidase regulatory protein; Nox organizer 1; Nox-organizing protein 1; SH3 and PX domain-containing protein 5
• Gene Name: NOXO1
• Related Disease:
  Colon cancer
  Colon carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Type-1/2 diabetes
  Adenocarcinoma
  Adenoma
  Signet ring cell carcinoma
  Gastritis
• UniProt ID: NOXO1_HUMAN
• PDB ID: 2L73
• Pfam ID: PF00018
• Sequence:
  MAGPRYPVSVQGAALVQIKRLQTFAFSVRWSDGSDTFVRRSWDEFRQLKKTLKETFPVEA
  GLLRRSDRVLPKLLGQASLDAPLLGRVGRTSRGLARLQLLETYSRRLLATAERVARSPTI
  TGFFAPQPLDLEPALPPGSRVILPTPEEQPLSRAAGRLSIHSLEAQSLRCLQPFCTQDTR
  DRPFQAQAQESLDVLLRHPSGWWLVENEDRQTAWFPAPYLEEAAPGQGREGGPSLGSSGP
  QFCASRAYESSRADELSVPAGARVRVLETSDRGWWLCRYGDRAGLLPAVLLRPEGLGALL
  SGTGFRGGDDPAGEARGFPEPSQATAPPPTVPTRPSPGAIQSRCCTVTRRALERRPRRQG
  RPRGCVDSVPHPTTEQ
• Function: Constitutively potentiates the superoxide-generating activity of NOX1 and NOX3 and is required for the biogenesis of otoconia/otolith, which are crystalline structures of the inner ear involved in the perception of gravity. Isoform 3 is more potent than isoform 1 in activating NOX3. Together with NOXA1, may also substitute to NCF1/p47phox and NCF2/p67phox in supporting the phagocyte NOX2/gp91phox superoxide-generating activity.
• Tissue Specificity: Expressed in testis, small and large intestines, liver, kidney and pancreas. Isoform 3 is mainly expressed in colon. Isoform 1 is preferentially expressed in testis.
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC3 GTPase cycle (R-HSA-9013423)
  WNT5 (R-HSA-9673324)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[2]
Lung carcinoma	DISTR26C	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[4]
Adenocarcinoma	DIS3IHTY	moderate	Biomarker	[5]
Adenoma	DIS78ZEV	moderate	Biomarker	[5]
Signet ring cell carcinoma	DISVCUCR	moderate	Altered Expression	[5]
Gastritis	DIS8G07K	Limited	Altered Expression	[3]

1 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 NADPH oxidase organizer 1 (NOXO1).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NADPH oxidase organizer 1 (NOXO1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of NADPH oxidase organizer 1 (NOXO1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of NADPH oxidase organizer 1 (NOXO1).	[9]
Marinol	DM70IK5	Approved	Marinol decreases the expression of NADPH oxidase organizer 1 (NOXO1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of NADPH oxidase organizer 1 (NOXO1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NADPH oxidase organizer 1 (NOXO1).	[12]

References

• [1] NADPH Oxidase 1 Activity and ROS Generation Are Regulated by Grb2/Cbl-Mediated Proteasomal Degradation of NoxO1 in Colon Cancer Cells.Cancer Res. 2016 Feb 15;76(4):855-65. doi: 10.1158/0008-5472.CAN-15-1512. Epub 2016 Jan 18.
• [2] Cerium oxide and barium sulfate nanoparticle inhalation affects gene expression in alveolar epithelial cells type II.J Nanobiotechnology. 2018 Feb 20;16(1):16. doi: 10.1186/s12951-018-0343-4.
• [3] NF-B-induced NOX1 activation promotes gastric tumorigenesis through the expansion of SOX2-positive epithelial cells.Oncogene. 2019 May;38(22):4250-4263. doi: 10.1038/s41388-019-0702-0. Epub 2019 Jan 30.
• [4] The NADPH organizers NoxO1 and p47phox are both mediators of diabetes-induced vascular dysfunction in mice.Redox Biol. 2018 May;15:12-21. doi: 10.1016/j.redox.2017.11.014. Epub 2017 Nov 22.
• [5] Evidence for cancer-associated expression of NADPH oxidase 1 (Nox1)-based oxidase system in the human stomach.Free Radic Biol Med. 2007 Dec 15;43(12):1627-38. doi: 10.1016/j.freeradbiomed.2007.08.029. Epub 2007 Sep 14.
• [6] 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.
• [7] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.