Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTFKK18)

• DOT Name: Collagen alpha-1(XV) chain (COL15A1)
• Synonyms: Collagen alpha-1(XV) chain
• Gene Name: COL15A1
• Related Disease:
  Classic Hodgkin lymphoma
  Anaplastic large cell lymphoma
  Arteriosclerosis
  Atherosclerosis
  Clear cell renal carcinoma
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  Neoplasm
  Neuromuscular disease
  Prostate cancer
  Prostate neoplasm
  Renal cell carcinoma
  Smith-McCort dysplasia 1
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Metastatic malignant neoplasm
  OPTN-related open angle glaucoma
  Basal laminar drusen
• UniProt ID: COFA1_HUMAN
• PDB ID: 3N3F
• Pfam ID: PF01391 ; PF20010 ; PF06482
• Sequence:
  MAPRRNNGQCWCLLMLLSVSTPLPAVTQTRGATETASQGHLDLTQLIGVPLPSSVSFVTG
  YGGFPAYSFGPGANVGRPARTLIPSTFFRDFAISVVVKPSSTRGGVLFAITDAFQKVIYL
  GLRLSGVEDGHQRIILYYTEPGSHVSQEAAAFSVPVMTHRWNRFAMIVQGEEVTLLVNCE
  EHSRIPFQRSSQALAFESSAGIFMGNAGATGLERFTGSLQQLTVHPDPRTPEELCDPEES
  SASGETSGLQEADGVAEILEAVTYTQASPKEAKVEPINTPPTPSSPFEDMELSGEPVPEG
  TLETTNMSIIQHSSPKQGSGEILNDTLEGVHSVDGDPITDSGSGAGAFLDIAEEKNLAAT
  AAGLAEVPISTAGEAEASSVPTGGPTLSMSTENPEEGVTPGPDNEERLAATAAGEAEALA
  SMPGEVEASGVAPGELDLSMSAQSLGEEATVGPSSEDSLTTAAAATEVSLSTFEDEEASG
  VPTDGLAPLTATMAPERAVTSGPGDEEDLAAATTEEPLITAGGEESGSPPPDGPPLPLPT
  VAPERWITPAQREHVGMKGQAGPKGEKGDAGEELPGPPEPSGPVGPTAGAEAEGSGLGWG
  SDVGSGSGDLVGSEQLLRGPPGPPGPPGLPGIPGKPGTDVFMGPPGSPGEDGPAGEPGPP
  GPEGQPGVDGATGLPGMKGEKGARGPNGSVGEKGDPGNRGLPGPPGKKGQAGPPGVMGPP
  GPPGPPGPPGPGCTMGLGFEDTEGSGSTQLLNEPKLSRPTAAIGLKGEKGDRGPKGERGM
  DGASIVGPPGPRGPPGHIKVLSNSLINITHGFMNFSDIPELVGPPGPDGLPGLPGFPGPR
  GPKGDTGLPGFPGLKGEQGEKGEPGAILTEDIPLERLMGKKGEPGMHGAPGPMGPKGPPG
  HKGEFGLPGRPGRPGLNGLKGTKGDPGVIMQGPPGLPGPPGPPGPPGAVINIKGAIFPIP
  VRPHCKMPVDTAHPGSPELITFHGVKGEKGSWGLPGSKGEKGDQGAQGPPGPPLDLAYLR
  HFLNNLKGENGDKGFKGEKGEKGDINGSFLMSGPPGLPGNPGPAGQKGETVVGPQGPPGA
  PGLPGPPGFGRPGDPGPPGPPGPPGPPAILGAAVALPGPPGPPGQPGLPGSRNLVTAFSN
  MDDMLQKAHLVIEGTFIYLRDSTEFFIRVRDGWKKLQLGELIPIPADSPPPPALSSNPHQ
  LLPPPNPISSANYEKPALHLAALNMPFSGDIRADFQCFKQARAAGLLSTYRAFLSSHLQD
  LSTIVRKAERYSLPIVNLKGQVLFNNWDSIFSGHGGQFNMHIPIYSFDGRDIMTDPSWPQ
  KVIWHGSSPHGVRLVDNYCEAWRTADTAVTGLASPLSTGKILDQKAYSCANRLIVLCIEN
  SFMTDARK
• Function: Structural protein that stabilizes microvessels and muscle cells, both in heart and in skeletal muscle; Restin potently inhibits angiogenesis.
• Tissue Specificity: Detected in fibroblasts and urine (at protein level) . Detected in placenta (at protein level) . Expressed predominantly in internal organs such as adrenal gland, pancreas and kidney.
• KEGG Pathway: Protein digestion and absorption (hsa04974)
• Reactome Pathway:
  Collagen biosynthesis and modifying enzymes (R-HSA-1650814)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)
  Collagen chain trimerization (R-HSA-8948216)
  Collagen degradation (R-HSA-1442490)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Classic Hodgkin lymphoma	DISV1LU6	Definitive	Biomarker	[1]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Altered Expression	[2]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[3]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[3]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[4]
Hepatitis	DISXXX35	Strong	Altered Expression	[5]
Hepatitis A virus infection	DISUMFQV	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Neuromuscular disease	DISQTIJZ	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[4]
Smith-McCort dysplasia 1	DIS8072R	Strong	Altered Expression	[9]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[10]
Breast cancer	DIS7DPX1	Disputed	Altered Expression	[11]
Breast carcinoma	DIS2UE88	Disputed	Altered Expression	[11]
Epithelial ovarian cancer	DIS56MH2	Disputed	Genetic Variation	[12]
Metastatic malignant neoplasm	DIS86UK6	Disputed	Altered Expression	[11]
OPTN-related open angle glaucoma	DISDR98A	Disputed	Genetic Variation	[13]
Basal laminar drusen	DISXZO3H	Limited	Genetic Variation	[14]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Collagen alpha-1(XV) chain (COL15A1) decreases the response to substance of Doxorubicin.	[27]
Methotrexate	DM2TEOL	Approved	Collagen alpha-1(XV) chain (COL15A1) decreases the response to substance of Methotrexate.	[27]
Etoposide	DMNH3PG	Approved	Collagen alpha-1(XV) chain (COL15A1) affects the response to substance of Etoposide.	[28]
Paclitaxel	DMLB81S	Approved	Collagen alpha-1(XV) chain (COL15A1) decreases the response to substance of Paclitaxel.	[27]
Topotecan	DMP6G8T	Approved	Collagen alpha-1(XV) chain (COL15A1) decreases the response to substance of Topotecan.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Collagen alpha-1(XV) chain (COL15A1).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Collagen alpha-1(XV) chain (COL15A1).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Collagen alpha-1(XV) chain (COL15A1).	[17]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Collagen alpha-1(XV) chain (COL15A1).	[18]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Collagen alpha-1(XV) chain (COL15A1).	[19]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Collagen alpha-1(XV) chain (COL15A1).	[20]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Collagen alpha-1(XV) chain (COL15A1).	[21]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Collagen alpha-1(XV) chain (COL15A1).	[22]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Collagen alpha-1(XV) chain (COL15A1).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Collagen alpha-1(XV) chain (COL15A1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Collagen alpha-1(XV) chain (COL15A1).	[26]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Collagen alpha-1(XV) chain (COL15A1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Collagen alpha-1(XV) chain (COL15A1).	[24]

References

• [1] Hodgkin and Reed-Sternberg cell-associated autoantigen CLIP-170/restin is a marker for dendritic cells and is involved in the trafficking of macropinosomes to the cytoskeleton, supporting a function-based concept of Hodgkin and Reed-Sternberg cells.Blood. 2002 Dec 1;100(12):4139-45. doi: 10.1182/blood.V100.12.4139.
• [2] Restin in Hodgkin's disease and anaplastic large cell lymphoma.Leuk Lymphoma. 1993 Dec;12(1-2):21-6. doi: 10.3109/10428199309059567.
• [3] Smooth muscle cell-specific deletion of Col15a1 unexpectedly leads to impaired development of advanced atherosclerotic lesions.Am J Physiol Heart Circ Physiol. 2017 May 1;312(5):H943-H958. doi: 10.1152/ajpheart.00029.2017. Epub 2017 Mar 10.
• [4] Identification of candidate tumour suppressor genes frequently methylated in renal cell carcinoma.Oncogene. 2010 Apr 8;29(14):2104-17. doi: 10.1038/onc.2009.493. Epub 2010 Feb 15.
• [5] Human collagen XV is a prominent histopathological component of sinusoidal capillarization in hepatocellular carcinogenesis.Int J Clin Oncol. 2016 Apr;21(2):302-309. doi: 10.1007/s10147-015-0888-2. Epub 2015 Aug 21.
• [6] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [7] Slow Muscle Precursors Lay Down a Collagen XV Matrix Fingerprint to Guide Motor Axon Navigation.J Neurosci. 2016 Mar 2;36(9):2663-76. doi: 10.1523/JNEUROSCI.2847-15.2016.
• [8] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [9] Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis.Hum Mol Genet. 2013 Dec 20;22(25):5107-20. doi: 10.1093/hmg/ddt365. Epub 2013 Aug 2.
• [10] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [11] Restin suppressed epithelial-mesenchymal transition and tumor metastasis in breast cancer cells through upregulating mir-200a/b expression via association with p73.Mol Cancer. 2015 May 14;14:102. doi: 10.1186/s12943-015-0370-9.
• [12] Genome-wide association study identifies new susceptibility loci for epithelial ovarian cancer in Han Chinese women.Nat Commun. 2014 Aug 19;5:4682. doi: 10.1038/ncomms5682.
• [13] Variations in COL15A1 and COL18A1 influence age of onset of primary open angle glaucoma.Clin Genet. 2013 Aug;84(2):167-74. doi: 10.1111/cge.12176. Epub 2013 May 27.
• [14] Whole Exome Sequencing in Patients with the Cuticular Drusen Subtype of Age-Related Macular Degeneration.PLoS One. 2016 Mar 23;11(3):e0152047. doi: 10.1371/journal.pone.0152047. eCollection 2016.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [19] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [20] 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.
• [21] The impact of luteal phase support on gene expression of extracellular matrix protein and adhesion molecules in the human endometrium during the window of implantation following controlled ovarian stimulation with a GnRH antagonist protocol. Fertil Steril. 2010 Nov;94(6):2264-71. doi: 10.1016/j.fertnstert.2010.01.068. Epub 2010 Mar 12.
• [22] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [23] The genomic response of a human uterine endometrial adenocarcinoma cell line to 17alpha-ethynyl estradiol. Toxicol Sci. 2009 Jan;107(1):40-55.
• [24] 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.
• [25] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [26] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [27] Microarray-based detection and expression analysis of extracellular matrix proteins in drug?resistant ovarian cancer cell lines. Oncol Rep. 2014 Nov;32(5):1981-90. doi: 10.3892/or.2014.3468. Epub 2014 Sep 9.
• [28] 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.