Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT74DWMV)

• DOT Name: SPARC-like protein 1 (SPARCL1)
• Synonyms: High endothelial venule protein; Hevin; MAST 9
• Gene Name: SPARCL1
• Related Disease:
  Abdominal aortic aneurysm
  Adult glioblastoma
  Alzheimer disease
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Chronic pancreatitis
  Clear cell renal carcinoma
  Colorectal neoplasm
  Epilepsy
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Lung neoplasm
  Matthew-Wood syndrome
  Metastatic malignant neoplasm
  Metastatic prostate carcinoma
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Stomach cancer
  Gastrointestinal stromal tumour
  Osteoarthritis
  Transitional cell carcinoma
  Urothelial carcinoma
  Bone osteosarcoma
  Endometriosis
  Osteosarcoma
  Breast cancer
  Breast carcinoma
  Pancreatic ductal carcinoma
  Pancreatic tumour
• UniProt ID: SPRL1_HUMAN
• PDB ID: 7KBU
• Pfam ID: PF09289 ; PF07648 ; PF10591
• Sequence:
  MKTGLFFLCLLGTAAAIPTNARLLSDHSKPTAETVAPDNTAIPSLRAEAEENEKETAVST
  EDDSHHKAEKSSVLKSKEESHEQSAEQGKSSSQELGLKDQEDSDGHLSVNLEYAPTEGTL
  DIKEDMSEPQEKKLSENTDFLAPGVSSFTDSNQQESITKREENQEQPRNYSHHQLNRSSK
  HSQGLRDQGNQEQDPNISNGEEEEEKEPGEVGTHNDNQERKTELPREHANSKQEEDNTQS
  DDILEESDQPTQVSKMQEDEFDQGNQEQEDNSNAEMEEENASNVNKHIQETEWQSQEGKT
  GLEAISNHKETEEKTVSEALLMEPTDDGNTTPRNHGVDDDGDDDGDDGGTDGPRHSASDD
  YFIPSQAFLEAERAQSIAYHLKIEEQREKVHENENIGTTEPGEHQEAKKAENSSNEEETS
  SEGNMRVHAVDSCMSFQCKRGHICKADQQGKPHCVCQDPVTCPPTKPLDQVCGTDNQTYA
  SSCHLFATKCRLEGTKKGHQLQLDYFGACKSIPTCTDFEVIQFPLRMRDWLKNILMQLYE
  ANSEHAGYLNEKQRNKVKKIYLDEKRLLAGDHPIDLLLRDFKKNYHMYVYPVHWQFSELD
  QHPMDRVLTHSELAPLRASLVPMEHCITRFFEECDPNKDKHITLKEWGHCFGIKEEDIDE
  NLLF
• Tissue Specificity: Highly expressed in lymph node, brain, heart, lung, skeletal muscle, ovary, small intestine, and colon, with lower levels in placenta, pancreas, testis, spleen, and thymus, and no expression in kidney, liver, and peripheral blood leukocytes.
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Chronic pancreatitis	DISBUOMJ	Strong	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[7]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[8]
Epilepsy	DISBB28L	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[11]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[13]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[6]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[14]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[15]
Pancreatic cancer	DISJC981	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[16]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[16]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[7]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Altered Expression	[17]
Osteoarthritis	DIS05URM	moderate	Biomarker	[18]
Transitional cell carcinoma	DISWVVDR	moderate	Posttranslational Modification	[4]
Urothelial carcinoma	DISRTNTN	moderate	Posttranslational Modification	[4]
Bone osteosarcoma	DIST1004	Disputed	Biomarker	[19]
Endometriosis	DISX1AG8	Disputed	Biomarker	[20]
Osteosarcoma	DISLQ7E2	Disputed	Biomarker	[19]
Breast cancer	DIS7DPX1	Limited	Biomarker	[21]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[21]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[6]
Pancreatic tumour	DIS3U0LK	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of SPARC-like protein 1 (SPARCL1).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of SPARC-like protein 1 (SPARCL1).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SPARC-like protein 1 (SPARCL1).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SPARC-like protein 1 (SPARCL1).	[25]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of SPARC-like protein 1 (SPARCL1).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of SPARC-like protein 1 (SPARCL1).	[27]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of SPARC-like protein 1 (SPARCL1).	[28]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of SPARC-like protein 1 (SPARCL1).	[29]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of SPARC-like protein 1 (SPARCL1).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of SPARC-like protein 1 (SPARCL1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of SPARC-like protein 1 (SPARCL1).	[30]
Cordycepin	DM72Y01	Investigative	Cordycepin decreases the expression of SPARC-like protein 1 (SPARCL1).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SPARC-like protein 1 (SPARCL1).	[26]

References

• [1] Microarray analysis to identify the similarities and differences of pathogenesis between aortic occlusive disease and abdominal aortic aneurysm.Vascular. 2018 Jun;26(3):301-314. doi: 10.1177/1708538117736695. Epub 2017 Oct 31.
• [2] Enhanced SPARCL1 expression in cancer stem cells improves preclinical modeling of glioblastoma by promoting both tumor infiltration and angiogenesis.Neurobiol Dis. 2020 Feb;134:104705. doi: 10.1016/j.nbd.2019.104705. Epub 2019 Dec 10.
• [3] Modulation of SPARC/Hevin Proteins in Alzheimer's Disease Brain Injury.J Alzheimers Dis. 2019;68(2):695-710. doi: 10.3233/JAD-181032.
• [4] Methylation of SPARCL1 Is Associated with Oncologic Outcome of Advanced Upper Urinary Tract Urothelial Carcinoma.Int J Mol Sci. 2019 Apr 3;20(7):1653. doi: 10.3390/ijms20071653.
• [5] Integrated analysis reveals down-regulation of SPARCL1 is correlated with cervical cancer development and progression.Cancer Biomark. 2018 Feb 6;21(2):355-365. doi: 10.3233/CBM-170501.
• [6] Tumor-suppressor function of SPARC-like protein 1/Hevin in pancreatic cancer.Neoplasia. 2007 Jan;9(1):8-17. doi: 10.1593/neo.06646.
• [7] SPARCL1 suppresses cell migration and invasion in renal cell carcinoma.Mol Med Rep. 2017 Nov;16(5):7784-7790. doi: 10.3892/mmr.2017.7535. Epub 2017 Sep 20.
• [8] Prognostic value of SPARCL1 in patients with colorectal cancer.Oncol Lett. 2018 Feb;15(2):1429-1434. doi: 10.3892/ol.2017.7511. Epub 2017 Dec 5.
• [9] The extracellular matrix protein SC1/hevin localizes to excitatory synapses following status epilepticus in the rat lithium-pilocarpine seizure model.J Neurosci Res. 2008 Oct;86(13):2895-905. doi: 10.1002/jnr.21735.
• [10] Down-regulated SPARCL1 is associated with clinical significance in human gastric cancer.J Surg Oncol. 2012 Jan;105(1):31-7. doi: 10.1002/jso.22025. Epub 2011 Aug 30.
• [11] The unique transcriptional activation domain of nuclear factor-I-X3 is critical to specifically induce marker gene expression in astrocytes.J Biol Chem. 2011 Mar 4;286(9):7315-26. doi: 10.1074/jbc.M110.152421. Epub 2010 Dec 28.
• [12] SPARC and Hevin expression correlate with tumour angiogenesis in hepatocellular carcinoma.J Pathol. 2006 Dec;210(4):459-68. doi: 10.1002/path.2068.
• [13] Evidence for transcriptional repression of SPARC-like 1, a gene downregulated in human lung tumors.Int J Oncol. 2004 Oct;25(4):1073-9.
• [14] SPARCL1 suppresses metastasis in prostate cancer.Mol Oncol. 2013 Dec;7(6):1019-30. doi: 10.1016/j.molonc.2013.07.008. Epub 2013 Jul 20.
• [15] Secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) is down regulated in aggressive prostate cancers and is prognostic for poor clinical outcome.Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14977-82. doi: 10.1073/pnas.1203525109. Epub 2012 Aug 27.
• [16] Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression.Cancer Res. 2015 Oct 15;75(20):4322-34. doi: 10.1158/0008-5472.CAN-15-0024. Epub 2015 Aug 20.
• [17] Secreted protein acidic and rich in cysteine-like 1 suppresses metastasis in gastric stromal tumors.BMC Gastroenterol. 2018 Jul 4;18(1):105. doi: 10.1186/s12876-018-0833-8.
• [18] Transcriptome comparison of meniscus from patients with and without osteoarthritis.Osteoarthritis Cartilage. 2018 Mar;26(3):422-432. doi: 10.1016/j.joca.2017.12.004. Epub 2017 Dec 16.
• [19] SPARCL1 suppresses osteosarcoma metastasis and recruits macrophages by activation of canonical WNT/-catenin signaling through stabilization of the WNT-receptor complex.Oncogene. 2018 Feb 22;37(8):1049-1061. doi: 10.1038/onc.2017.403. Epub 2017 Oct 30.
• [20] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [21] Clinicopathological significance of reduced SPARCL1 expression in human breast cancer.Asian Pac J Cancer Prev. 2013;14(1):195-200. doi: 10.7314/apjcp.2013.14.1.195.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [27] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [28] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [29] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [30] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [31] Cordycepin inhibits the proliferation and progression of NPC by targeting the MAPK/ERK and -catenin pathways. Oncol Lett. 2022 Jan;23(1):20. doi: 10.3892/ol.2021.13138. Epub 2021 Nov 16.