Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3ZJ0XU)

• DOT Name: Platelet-derived growth factor C (PDGFC)
• Synonyms: PDGF-C; Fallotein; Spinal cord-derived growth factor; SCDGF; VEGF-E
• Gene Name: PDGFC
• UniProt ID: PDGFC_HUMAN
• Pfam ID: PF00431 ; PF00341
• Sequence:
  MSLFGLLLLTSALAGQRQGTQAESNLSSKFQFSSNKEQNGVQDPQHERIITVSTNGSIHS
  PRFPHTYPRNTVLVWRLVAVEENVWIQLTFDERFGLEDPEDDICKYDFVEVEEPSDGTIL
  GRWCGSGTVPGKQISKGNQIRIRFVSDEYFPSEPGFCIHYNIVMPQFTEAVSPSVLPPSA
  LPLDLLNNAITAFSTLEDLIRYLEPERWQLDLEDLYRPTWQLLGKAFVFGRKSRVVDLNL
  LTEEVRLYSCTPRNFSVSIREELKRTDTIFWPGCLLVKRCGGNCACCLHNCNECQCVPSK
  VTKKYHEVLQLRPKTGVRGLHKSLTDVALEHHEECDCVCRGSTGG
• Function: Growth factor that plays an essential role in the regulation of embryonic development, cell proliferation, cell migration, survival and chemotaxis. Potent mitogen and chemoattractant for cells of mesenchymal origin. Required for normal skeleton formation during embryonic development, especially for normal development of the craniofacial skeleton and for normal development of the palate. Required for normal skin morphogenesis during embryonic development. Plays an important role in wound healing, where it appears to be involved in three stages: inflammation, proliferation and remodeling. Plays an important role in angiogenesis and blood vessel development. Involved in fibrotic processes, in which transformation of interstitial fibroblasts into myofibroblasts plus collagen deposition occurs. The CUB domain has mitogenic activity in coronary artery smooth muscle cells, suggesting a role beyond the maintenance of the latency of the PDGF domain. In the nucleus, PDGFC seems to have additional function.
• Tissue Specificity: Expressed in the fallopian tube, vascular smooth muscle cells in kidney, breast and colon and in visceral smooth muscle of the gastrointestinal tract. Highly expressed in retinal pigment epithelia. Expressed in medulloblastoma. In the kidney, constitutively expressed in parietal epithelial cells of Bowman's capsule, tubular epithelial cells and in arterial endothelial cells (at protein level). Highly expressed in the platelets, prostate, testis and uterus. Higher expression is observed in uterine leiomyomata. Weaker expression in the spleen, thymus, heart, pancreas, liver, ovary cells and small intestine, and negligible expression in the colon and peripheral blood leukocytes.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Calcium sig.ling pathway (hsa04020)
  Phospholipase D sig.ling pathway (hsa04072)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  Regulation of actin cytoskeleton (hsa04810)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Choline metabolism in cancer (hsa05231)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Platelet-derived growth factor C (PDGFC) affects the response to substance of Etoposide.	[18]
Topotecan	DMP6G8T	Approved	Platelet-derived growth factor C (PDGFC) affects the response to substance of Topotecan.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Platelet-derived growth factor C (PDGFC).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Platelet-derived growth factor C (PDGFC).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Platelet-derived growth factor C (PDGFC).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Platelet-derived growth factor C (PDGFC).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Platelet-derived growth factor C (PDGFC).	[4]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Platelet-derived growth factor C (PDGFC).	[5]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Platelet-derived growth factor C (PDGFC).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Platelet-derived growth factor C (PDGFC).	[7]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Platelet-derived growth factor C (PDGFC).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Platelet-derived growth factor C (PDGFC).	[9]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Platelet-derived growth factor C (PDGFC).	[10]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Platelet-derived growth factor C (PDGFC).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Platelet-derived growth factor C (PDGFC).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Platelet-derived growth factor C (PDGFC).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Platelet-derived growth factor C (PDGFC).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Platelet-derived growth factor C (PDGFC).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Platelet-derived growth factor C (PDGFC).	[16]
I-BET151	DMYRUH2	Investigative	I-BET151 decreases the expression of Platelet-derived growth factor C (PDGFC).	[17]
PFI-1	DMVFK3J	Investigative	PFI-1 decreases the expression of Platelet-derived growth factor C (PDGFC).	[17]

References

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• [2] 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.
• [3] 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.
• [4] 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.
• [5] Prenatal arsenic exposure and shifts in the newborn proteome: interindividual differences in tumor necrosis factor (TNF)-responsive signaling. Toxicol Sci. 2014 Jun;139(2):328-37. doi: 10.1093/toxsci/kfu053. Epub 2014 Mar 27.
• [6] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [7] 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.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] 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.
• [10] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [11] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [12] 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.
• [13] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] 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.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] BRD4 is a novel therapeutic target for liver fibrosis. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15713-8. doi: 10.1073/pnas.1522163112. Epub 2015 Dec 7.
• [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.