Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKPL09B)

• DOT Name: V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C)
• Synonyms: V-ATPase 16 kDa proteolipid subunit c; Vacuolar proton pump 16 kDa proteolipid subunit c
• Gene Name: ATP6V0C
• Related Disease:
  Advanced cancer
  Carcinoma of esophagus
  Cytomegalovirus infection
  Esophageal cancer
  Hepatocellular carcinoma
  Neoplasm of esophagus
  Neoplasm
  Colorectal carcinoma
  Infantile spasm
  Metastatic malignant neoplasm
  Prostate cancer
  Prostate carcinoma
• UniProt ID: VATL_HUMAN
• PDB ID: 6WLW; 6WM2; 6WM3; 6WM4; 7U4T; 7UNF
• Pfam ID: PF00137
• Sequence:
  MSESKSGPEYASFFAVMGASAAMVFSALGAAYGTAKSGTGIAAMSVMRPEQIMKSIIPVV
  MAGIIAIYGLVVAVLIANSLNDDISLYKSFLQLGAGLSVGLSGLAAGFAIGIVGDAGVRG
  TAQQPRLFVGMILILIFAEVLGLYGLIVALILSTK
• Function: Proton-conducting pore forming subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons. V-ATPase is responsible for acidifying and maintaining the pH of intracellular compartments and in some cell types, is targeted to the plasma membrane, where it is responsible for acidifying the extracellular environment.
• KEGG Pathway:
  Oxidative phosphorylation (hsa00190)
  Metabolic pathways (hsa01100)
  Lysosome (hsa04142)
  Phagosome (hsa04145)
  Sy.ptic vesicle cycle (hsa04721)
  Collecting duct acid secretion (hsa04966)
  Vibrio cholerae infection (hsa05110)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Tuberculosis (hsa05152)
  Human papillomavirus infection (hsa05165)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Insulin receptor recycling (R-HSA-77387)
  Transferrin endocytosis and recycling (R-HSA-917977)
  Amino acids regulate mTORC1 (R-HSA-9639288)
  Ion channel transport (R-HSA-983712)
  ROS and RNS production in phagocytes (R-HSA-1222556)
• BioCyc Pathway: MetaCyc:MONOMER66-34368

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[2]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[3]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	moderate	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[5]
Infantile spasm	DISZSKDG	Limited	Autosomal dominant	[6]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[1]
Prostate cancer	DISF190Y	Limited	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[1]

12 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 V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[10]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[11]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[12]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[13]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[15]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[18]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of V-type proton ATPase 16 kDa proteolipid subunit c (ATP6V0C).	[16]

References

• [1] Silencing of vacuolar ATPase csubunit ATP6V0C inhibits the invasion of prostate cancer cells through a LASS2/TMSG1-independent manner.Oncol Rep. 2018 Jan;39(1):298-306. doi: 10.3892/or.2017.6092. Epub 2017 Nov 10.
• [2] Vacuolar H(+)-ATPase Subunit V0C Regulates Aerobic Glycolysis of Esophageal Cancer Cells via PKM2 Signaling.Cells. 2019 Sep 24;8(10):1137. doi: 10.3390/cells8101137.
• [3] Cellular v-ATPase is required for virion assembly compartment formation in human cytomegalovirus infection.Open Biol. 2017 Nov;7(11):160298. doi: 10.1098/rsob.160298.
• [4] Expression and functional role of vacuolar H(+)-ATPase in human hepatocellular carcinoma.Carcinogenesis. 2012 Dec;33(12):2432-40. doi: 10.1093/carcin/bgs277. Epub 2012 Sep 7.
• [5] ATP6L promotes metastasis of colorectal cancer by inducing epithelial-mesenchymal transition.Cancer Sci. 2020 Feb;111(2):477-488. doi: 10.1111/cas.14283. Epub 2020 Jan 6.
• [6] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] 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.
• [10] 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.
• [11] Combined effects of arsenic and palmitic acid on oxidative stress and lipid metabolism disorder in human hepatoma HepG2 cells. Sci Total Environ. 2021 May 15;769:144849. doi: 10.1016/j.scitotenv.2020.144849. Epub 2021 Jan 19.
• [12] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [13] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [14] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [18] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [19] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.