Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC06MY4)

• DOT Name: Spondin-1 (SPON1)
• Synonyms: F-spondin; Vascular smooth muscle cell growth-promoting factor
• Gene Name: SPON1
• Related Disease:
  Non-insulin dependent diabetes
  Cardiac failure
  Chronic kidney disease
  Congestive heart failure
  Endometrial cancer
  Endometrial carcinoma
  Osteoarthritis
  Bone osteosarcoma
  Osteosarcoma
  Dementia
• UniProt ID: SPON1_HUMAN
• PDB ID: 2ZOT; 2ZOU; 3COO; 3Q13
• Pfam ID: PF02014 ; PF06468 ; PF19028 ; PF00090
• Sequence:
  MRLSPAPLKLSRTPALLALALPLAAALAFSDETLDKVPKSEGYCSRILRAQGTRREGYTE
  FSLRVEGDPDFYKPGTSYRVTLSAAPPSYFRGFTLIALRENREGDKEEDHAGTFQIIDEE
  ETQFMSNCPVAVTESTPRRRTRIQVFWIAPPAGTGCVILKASIVQKRIIYFQDEGSLTKK
  LCEQDSTFDGVTDKPILDCCACGTAKYRLTFYGNWSEKTHPKDYPRRANHWSAIIGGSHS
  KNYVLWEYGGYASEGVKQVAELGSPVKMEEEIRQQSDEVLTVIKAKAQWPAWQPLNVRAA
  PSAEFSVDRTRHLMSFLTMMGPSPDWNVGLSAEDLCTKECGWVQKVVQDLIPWDAGTDSG
  VTYESPNKPTIPQEKIRPLTSLDHPQSPFYDPEGGSITQVARVVIERIARKGEQCNIVPD
  NVDDIVADLAPEEKDEDDTPETCIYSNWSPWSACSSSTCDKGKRMRQRMLKAQLDLSVPC
  PDTQDFQPCMGPGCSDEDGSTCTMSEWITWSPCSISCGMGMRSRERYVKQFPEDGSVCTL
  PTEETEKCTVNEECSPSSCLMTEWGEWDECSATCGMGMKKRHRMIKMNPADGSMCKAETS
  QAEKCMMPECHTIPCLLSPWSEWSDCSVTCGKGMRTRQRMLKSLAELGDCNEDLEQVEKC
  MLPECPIDCELTEWSQWSECNKSCGKGHVIRTRMIQMEPQFGGAPCPETVQRKKCRIRKC
  LRNPSIQKLRWREARESRRSEQLKEESEGEQFPGCRMRPWTAWSECTKLCGGGIQERYMT
  VKKRFKSSQFTSCKDKKEIRACNVHPC
• Function: Cell adhesion protein that promotes the attachment of spinal cord and sensory neuron cells and the outgrowth of neurites in vitro. May contribute to the growth and guidance of axons in both the spinal cord and the PNS. Major factor for vascular smooth muscle cell.
• Tissue Specificity: Highest expression in lung, lower expression in brain, heart, kidney, liver and testis, and lowest expression in pancreas, skeletal muscle and ovary. Not expressed in spleen.
• Reactome Pathway:
  O-glycosylation of TSR domain-containing proteins (R-HSA-5173214)
  Defective B3GALTL causes PpS (R-HSA-5083635)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[2]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[2]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[4]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[4]
Osteoarthritis	DIS05URM	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[6]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[6]
Dementia	DISXL1WY	Limited	Genetic Variation	[7]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Spondin-1 (SPON1) affects the response to substance of Cisplatin.	[18]
Mitoxantrone	DMM39BF	Approved	Spondin-1 (SPON1) affects the response to substance of Mitoxantrone.	[18]

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 Spondin-1 (SPON1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Spondin-1 (SPON1).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Spondin-1 (SPON1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Spondin-1 (SPON1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Spondin-1 (SPON1).	[11]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Spondin-1 (SPON1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Spondin-1 (SPON1).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Spondin-1 (SPON1).	[14]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Spondin-1 (SPON1).	[13]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Spondin-1 (SPON1).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Spondin-1 (SPON1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Spondin-1 (SPON1).	[16]

References

• [1] Proteomic analysis reveals downregulation of housekeeping proteins in the diabetic vascular proteome.Acta Diabetol. 2017 Feb;54(2):171-190. doi: 10.1007/s00592-016-0929-y. Epub 2016 Oct 28.
• [2] Circulating proteins as predictors of incident heart failure in the elderly.Eur J Heart Fail. 2018 Jan;20(1):55-62. doi: 10.1002/ejhf.980. Epub 2017 Oct 2.
• [3] Proteomic analysis of heart failure hospitalization among patients with chronic kidney disease: The Heart and Soul Study.PLoS One. 2018 Dec 17;13(12):e0208042. doi: 10.1371/journal.pone.0208042. eCollection 2018.
• [4] F-Spondin Is the Signal by Which 2-Methoxyestradiol Induces Apoptosis in the Endometrial Cancer Cell Line Ishikawa.Int J Mol Sci. 2019 Aug 7;20(16):3850. doi: 10.3390/ijms20163850.
• [5] F-spondin, a neuroregulatory protein, is up-regulated in osteoarthritis and regulates cartilage metabolism via TGF-beta activation.FASEB J. 2009 Jan;23(1):79-89. doi: 10.1096/fj.08-114363. Epub 2008 Sep 9.
• [6] Spondin 1 promotes metastatic progression through Fak and Src dependent pathway in human osteosarcoma.Biochem Biophys Res Commun. 2015 Aug 14;464(1):45-50. doi: 10.1016/j.bbrc.2015.05.092. Epub 2015 May 29.
• [7] Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity.Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4768-73. doi: 10.1073/pnas.1216206110. Epub 2013 Mar 5.
• [8] 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.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [10] 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.
• [11] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [12] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [13] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [14] Cell-type-specific responses to chemotherapeutics in breast cancer. Cancer Res. 2004 Jun 15;64(12):4218-26.
• [15] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] 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.
• [18] 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.