Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC498N5)

• DOT Name: Protein kinase C eta type (PRKCH)
• Synonyms: EC 2.7.11.13; PKC-L; nPKC-eta
• Gene Name: PRKCH
• UniProt ID: KPCL_HUMAN
• PDB ID: 2FK9; 3TXO; 8FP1; 8FP3
• EC Number: 2.7.11.13
• Pfam ID: PF00130 ; PF00168 ; PF00069 ; PF00433
• Sequence:
  MSSGTMKFNGYLRVRIGEAVGLQPTRWSLRHSLFKKGHQLLDPYLTVSVDQVRVGQTSTK
  QKTNKPTYNEEFCANVTDGGHLELAVFHETPLGYDHFVANCTLQFQELLRTTGASDTFEG
  WVDLEPEGKVFVVITLTGSFTEATLQRDRIFKHFTRKRQRAMRRRVHQINGHKFMATYLR
  QPTYCSHCREFIWGVFGKQGYQCQVCTCVVHKRCHHLIVTACTCQNNINKVDSKIAEQRF
  GINIPHKFSIHNYKVPTFCDHCGSLLWGIMRQGLQCKICKMNVHIRCQANVAPNCGVNAV
  ELAKTLAGMGLQPGNISPTSKLVSRSTLRRQGKESSKEGNGIGVNSSNRLGIDNFEFIRV
  LGKGSFGKVMLARVKETGDLYAVKVLKKDVILQDDDVECTMTEKRILSLARNHPFLTQLF
  CCFQTPDRLFFVMEFVNGGDLMFHIQKSRRFDEARARFYAAEIISALMFLHDKGIIYRDL
  KLDNVLLDHEGHCKLADFGMCKEGICNGVTTATFCGTPDYIAPEILQEMLYGPAVDWWAM
  GVLLYEMLCGHAPFEAENEDDLFEAILNDEVVYPTWLHEDATGILKSFMTKNPTMRLGSL
  TQGGEHAILRHPFFKEIDWAQLNHRQIEPPFRPRIKSREDVSNFDPDFIKEEPVLTPIDE
  GHLPMINQDEFRNFSYVSPELQP
• Function: Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in the regulation of cell differentiation in keratinocytes and pre-B cell receptor, mediates regulation of epithelial tight junction integrity and foam cell formation, and is required for glioblastoma proliferation and apoptosis prevention in MCF-7 cells. In keratinocytes, binds and activates the tyrosine kinase FYN, which in turn blocks epidermal growth factor receptor (EGFR) signaling and leads to keratinocyte growth arrest and differentiation. Associates with the cyclin CCNE1-CDK2-CDKN1B complex and inhibits CDK2 kinase activity, leading to RB1 dephosphorylation and thereby G1 arrest in keratinocytes. In association with RALA activates actin depolymerization, which is necessary for keratinocyte differentiation. In the pre-B cell receptor signaling, functions downstream of BLNK by up-regulating IRF4, which in turn activates L chain gene rearrangement. Regulates epithelial tight junctions (TJs) by phosphorylating occludin (OCLN) on threonine residues, which is necessary for the assembly and maintenance of TJs. In association with PLD2 and via TLR4 signaling, is involved in lipopolysaccharide (LPS)-induced RGS2 down-regulation and foam cell formation. Upon PMA stimulation, mediates glioblastoma cell proliferation by activating the mTOR pathway, the PI3K/AKT pathway and the ERK1-dependent phosphorylation of ELK1. Involved in the protection of glioblastoma cells from irradiation-induced apoptosis by preventing caspase-9 activation. In camptothecin-treated MCF-7 cells, regulates NF-kappa-B upstream signaling by activating IKBKB, and confers protection against DNA damage-induced apoptosis. Promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria. Phosphorylates ATF2 which promotes its nuclear retention and transcriptional activity and negatively regulates its mitochondrial localization.
• Tissue Specificity: Most abundant in lung, less in heart and skin.
• KEGG Pathway:
  Vascular smooth muscle contraction (hsa04270)
  Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway:
  G alpha (z) signalling events (R-HSA-418597)
  Effects of PIP2 hydrolysis (R-HSA-114508)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Protein kinase C eta type (PRKCH) decreases the response to substance of Rapamycin Immunosuppressant Drug.	[11]

19 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 Protein kinase C eta type (PRKCH).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein kinase C eta type (PRKCH).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein kinase C eta type (PRKCH).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein kinase C eta type (PRKCH).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Protein kinase C eta type (PRKCH).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein kinase C eta type (PRKCH).	[6]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Protein kinase C eta type (PRKCH).	[7]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Protein kinase C eta type (PRKCH).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein kinase C eta type (PRKCH).	[6]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Protein kinase C eta type (PRKCH).	[9]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Protein kinase C eta type (PRKCH).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein kinase C eta type (PRKCH).	[6]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the activity of Protein kinase C eta type (PRKCH).	[11]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Protein kinase C eta type (PRKCH).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein kinase C eta type (PRKCH).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Protein kinase C eta type (PRKCH).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein kinase C eta type (PRKCH).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein kinase C eta type (PRKCH).	[19]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Protein kinase C eta type (PRKCH).	[20]

3 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 decreases the methylation of Protein kinase C eta type (PRKCH).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein kinase C eta type (PRKCH).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Protein kinase C eta type (PRKCH).	[18]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] The RET oncogene is a critical component of transcriptional programs associated with retinoic acid-induced differentiation in neuroblastoma. Mol Cancer Ther. 2007 Apr;6(4):1300-9.
• [3] 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.
• [4] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [5] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [6] 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.
• [7] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [8] 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.
• [9] Overexpression of protein kinase C-beta1 isoenzyme suppresses indomethacin-induced apoptosis in gastric epithelial cells. Gastroenterology. 2000 Mar;118(3):507-14. doi: 10.1016/s0016-5085(00)70256-3.
• [10] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [11] Phorbol 12-myristate 13-acetate and serum synergize to promote rapamycin-insensitive cell proliferation via protein kinase C-eta. Oncogene. 2007 Jan 18;26(3):407-14. doi: 10.1038/sj.onc.1209791. Epub 2006 Jul 10.
• [12] 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.
• [13] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [14] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.
• [17] 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.
• [18] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.