Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2CXM6L)

• DOT Name: Platelet factor 4 variant (PF4V1)
• Synonyms: C-X-C motif chemokine 4 variant; CXCL4L1; PF4alt; PF4var1
• Gene Name: PF4V1
• Related Disease:
  Type-1 diabetes
  Type-1/2 diabetes
  Advanced cancer
  Endometriosis
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Vascular disease
  Autoimmune polyendocrinopathy
  Cardiac disease
  Coronary atherosclerosis
  Coronary heart disease
  Kaposi sarcoma
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
• UniProt ID: PF4V_HUMAN
• PDB ID: 4HSV
• Pfam ID: PF00048
• Sequence:
  MSSAARSRLTRATRQEMLFLALLLLPVVVAFARAEAEEDGDLQCLCVKTTSQVRPRHITS
  LEVIKAGPHCPTAQLIATLKNGRKICLDLQALLYKKIIKEHLES
• Function: Inhibitor of angiogenesis. Inhibitor of endothelial cell chemotaxis (in vitro).
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  Viral protein interaction with cytokine and cytokine receptor (hsa04061)
  Chemokine sig.ling pathway (hsa04062)
• Reactome Pathway:
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Common Pathway of Fibrin Clot Formation (R-HSA-140875)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1 diabetes	DIS7HLUB	Definitive	Genetic Variation	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Endometriosis	DISX1AG8	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Vascular disease	DISVS67S	Strong	Biomarker	[6]
Autoimmune polyendocrinopathy	DISOLDB2	Limited	Biomarker	[7]
Cardiac disease	DISVO1I5	Limited	Biomarker	[8]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[8]
Coronary heart disease	DIS5OIP1	Limited	Biomarker	[8]
Kaposi sarcoma	DISC1H1Z	Limited	Biomarker	[9]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[10]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Biomarker	[10]

5 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 Platelet factor 4 variant (PF4V1).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Platelet factor 4 variant (PF4V1).	[12]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Platelet factor 4 variant (PF4V1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Platelet factor 4 variant (PF4V1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Platelet factor 4 variant (PF4V1).	[11]

References

• [1] CXCL4L1 Promoter Polymorphisms Are Associated with Improved Renal Function in Type 1 Diabetes.J Immunol. 2019 Feb 1;202(3):912-919. doi: 10.4049/jimmunol.1801086. Epub 2018 Dec 28.
• [2] PF4V1, an miRNA-875-3p target, suppresses cell proliferation, migration, and invasion in prostate cancer and serves as a potential prognostic biomarker.Cancer Manag Res. 2019 Mar 21;11:2299-2312. doi: 10.2147/CMAR.S187831. eCollection 2019.
• [3] Impaired CXCL4 expression in tumor-associated macrophages (TAMs) of ovarian cancers arising in endometriosis.Cancer Biol Ther. 2012 Jun;13(8):671-80. doi: 10.4161/cbt.20084. Epub 2012 Jun 1.
• [4] Potential Markers from Serum-Purified Exosomes for Detecting Oral Squamous Cell Carcinoma Metastasis.Cancer Epidemiol Biomarkers Prev. 2019 Oct;28(10):1668-1681. doi: 10.1158/1055-9965.EPI-18-1122. Epub 2019 Jul 26.
• [5] Downregulation of serum CXCL4L1 predicts progression and poor prognosis in prostate cancer patients treated by radical prostatectomy.Asian J Androl. 2019 Jul-Aug;21(4):387-392. doi: 10.4103/aja.aja_117_18.
• [6] Platelets release CXCL4L1, a nonallelic variant of the chemokine platelet factor-4/CXCL4 and potent inhibitor of angiogenesis.Circ Res. 2004 Oct 29;95(9):855-7. doi: 10.1161/01.RES.0000146674.38319.07. Epub 2004 Sep 30.
• [7] The role of platelets in antiphospholipid syndrome.Platelets. 2017 Dec;28(8):762-766. doi: 10.1080/09537104.2017.1280150. Epub 2017 Mar 7.
• [8] PF-4var/CXCL4L1 predicts outcome in stable coronary artery disease patients with preserved left ventricular function.PLoS One. 2012;7(2):e31343. doi: 10.1371/journal.pone.0031343. Epub 2012 Feb 23.
• [9] Recombinant Parvoviruses Armed to Deliver CXCL4L1 and CXCL10 Are Impaired in Their Antiangiogenic and Antitumoral Effects in a Kaposi Sarcoma Tumor Model Due To the Chemokines' Interference with the Virus Cycle.Hum Gene Ther. 2017 Mar;28(3):295-306. doi: 10.1089/hum.2016.108. Epub 2016 Dec 29.
• [10] Dual Roles for CXCL4 Chemokines and CXCR3 in Angiogenesis and Invasion of Pancreatic Cancer.Cancer Res. 2016 Nov 15;76(22):6507-6519. doi: 10.1158/0008-5472.CAN-15-2864. Epub 2016 Sep 9.
• [11] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [14] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.