Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTT23UM3)

• DOT Name: Mesothelin (MSLN)
• Synonyms: CAK1 antigen; Pre-pro-megakaryocyte-potentiating factor
• Gene Name: MSLN
• UniProt ID: MSLN_HUMAN
• PDB ID: 4F3F; 7U8C; 7U9J; 7UED; 8CX3; 8CXC; 8CYH; 8CZ8
• Pfam ID: PF06060
• Sequence:
  MALPTARPLLGSCGTPALGSLLFLLFSLGWVQPSRTLAGETGQEAAPLDGVLANPPNISS
  LSPRQLLGFPCAEVSGLSTERVRELAVALAQKNVKLSTEQLRCLAHRLSEPPEDLDALPL
  DLLLFLNPDAFSGPQACTRFFSRITKANVDLLPRGAPERQRLLPAALACWGVRGSLLSEA
  DVRALGGLACDLPGRFVAESAEVLLPRLVSCPGPLDQDQQEAARAALQGGGPPYGPPSTW
  SVSTMDALRGLLPVLGQPIIRSIPQGIVAAWRQRSSRDPSWRQPERTILRPRFRREVEKT
  ACPSGKKAREIDESLIFYKKWELEACVDAALLATQMDRVNAIPFTYEQLDVLKHKLDELY
  PQGYPESVIQHLGYLFLKMSPEDIRKWNVTSLETLKALLEVNKGHEMSPQAPRRPLPQVA
  TLIDRFVKGRGQLDKDTLDTLTAFYPGYLCSLSPEELSSVPPSSIWAVRPQDLDTCDPRQ
  LDVLYPKARLAFQNMNGSEYFVKIQSFLGGAPTEDLKALSQQNVSMDLATFMKLRTDAVL
  PLTVAEVQKLLGPHVEGLKAEERHRPVRDWILRQRQDDLDTLGLGLQGGIPNGYLVLDLS
  MQEALSGTPCLLGPGPVLTVLALLLASTLA
• Function: Membrane-anchored forms may play a role in cellular adhesion.; Megakaryocyte-potentiating factor (MPF) potentiates megakaryocyte colony formation in vitro.
• Tissue Specificity: Expressed in lung. Expressed at low levels in heart, placenta and kidney. Expressed in mesothelial cells. Highly expressed in mesotheliomas, ovarian cancers, and some squamous cell carcinomas (at protein level).
• Reactome Pathway:
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Post-translational protein phosphorylation (R-HSA-8957275)
  Post-translational modification (R-HSA-163125)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Mesothelin (MSLN) affects the response to substance of Methotrexate.	[12]

2 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 Mesothelin (MSLN).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Mesothelin (MSLN).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mesothelin (MSLN).	[2]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Mesothelin (MSLN).	[3]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Mesothelin (MSLN).	[4]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Mesothelin (MSLN).	[5]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Mesothelin (MSLN).	[6]
Epanova	DMHEAGL	Approved	Epanova decreases the expression of Mesothelin (MSLN).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mesothelin (MSLN).	[8]
TAK-114	DMTXE19	Phase 1	TAK-114 decreases the expression of Mesothelin (MSLN).	[10]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Mesothelin (MSLN).	[11]

References

• [1] 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.
• [2] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [6] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [7] Differential effects of omega-3 and omega-6 Fatty acids on gene expression in breast cancer cells. Breast Cancer Res Treat. 2007 Jan;101(1):7-16. doi: 10.1007/s10549-006-9269-x. Epub 2006 Jul 6.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] Natura-alpha targets forkhead box m1 and inhibits androgen-dependent and -independent prostate cancer growth and invasion. Clin Cancer Res. 2011 Jul 1;17(13):4414-24. doi: 10.1158/1078-0432.CCR-11-0431. Epub 2011 May 23.
• [11] 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.
• [12] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.