Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPL1HRB)

• DOT Name: Plakophilin-3 (PKP3)
• Gene Name: PKP3
• Related Disease:
  Bladder cancer
  Carcinoma
  Epithelial ovarian cancer
  Melanoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate neoplasm
  Tuberculosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Autoimmune disease
  Pemphigus vulgaris
  Non-small-cell lung cancer
  Digestive system neoplasm
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Malignant mesothelioma
  Malignant pleural mesothelioma
  Nasopharyngeal carcinoma
• UniProt ID: PKP3_HUMAN
• Pfam ID: PF00514
• Sequence:
  MQDGNFLLSALQPEAGVCSLALPSDLQLDRRGAEGPEAERLRAARVQEQVRARLLQLGQQ
  PRHNGAAEPEPEAETARGTSRGQYHTLQAGFSSRSQGLSGDKTSGFRPIAKPAYSPASWS
  SRSAVDLSCSRRLSSAHNGGSAFGAAGYGGAQPTPPMPTRPVSFHERGGVGSRADYDTLS
  LRSLRLGPGGLDDRYSLVSEQLEPAATSTYRAFAYERQASSSSSRAGGLDWPEATEVSPS
  RTIRAPAVRTLQRFQSSHRSRGVGGAVPGAVLEPVARAPSVRSLSLSLADSGHLPDVHGF
  NSYGSHRTLQRLSSGFDDIDLPSAVKYLMASDPNLQVLGAAYIQHKCYSDAAAKKQARSL
  QAVPRLVKLFNHANQEVQRHATGAMRNLIYDNADNKLALVEENGIFELLRTLREQDDELR
  KNVTGILWNLSSSDHLKDRLARDTLEQLTDLVLSPLSGAGGPPLIQQNASEAEIFYNATG
  FLRNLSSASQATRQKMRECHGLVDALVTSINHALDAGKCEDKSVENAVCVLRNLSYRLYD
  EMPPSALQRLEGRGRRDLAGAPPGEVVGCFTPQSRRLRELPLAADALTFAEVSKDPKGLE
  WLWSPQIVGLYNRLLQRCELNRHTTEAAAGALQNITAGDRRWAGVLSRLALEQERILNPL
  LDRVRTADHHQLRSLTGLIRNLSRNARNKDEMSTKVVSHLIEKLPGSVGEKSPPAEVLVN
  IIAVLNNLVVASPIAARDLLYFDGLRKLIFIKKKRDSPDSEKSSRAASSLLANLWQYNKL
  HRDFRAKGYRKEDFLGP
• Function: May play a role in junctional plaques.
• Tissue Specificity: Isoform PKP3a is found in desmosomes of most simple and stratified epithelia. Not found in foreskin fibroblasts and various sarcoma-derived cell lines. Beside dendritic reticular cells of lymphatic follicles not found in non-epithelial desmosome-bearing tissues. Isoform PKP3b is abundant in the desmosomes of stratified epithelial cell but absent in simple epithelial cells, it is also expressed in the colon and its tumors.
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[3]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[5]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[6]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[1]
Autoimmune disease	DISORMTM	moderate	Biomarker	[7]
Pemphigus vulgaris	DISENR62	moderate	Posttranslational Modification	[7]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Altered Expression	[8]
Digestive system neoplasm	DISPOJCT	Limited	Altered Expression	[9]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[8]
Lung cancer	DISCM4YA	Limited	Biomarker	[8]
Lung carcinoma	DISTR26C	Limited	Biomarker	[8]
Malignant mesothelioma	DISTHJGH	Limited	Biomarker	[10]
Malignant pleural mesothelioma	DIST2R60	Limited	Altered Expression	[10]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[11]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Plakophilin-3 (PKP3) affects the response to substance of Temozolomide.	[20]
Arsenic trioxide	DM61TA4	Approved	Plakophilin-3 (PKP3) decreases the response to substance of Arsenic trioxide.	[21]
DTI-015	DMXZRW0	Approved	Plakophilin-3 (PKP3) affects the response to substance of DTI-015.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Plakophilin-3 (PKP3).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Plakophilin-3 (PKP3).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Plakophilin-3 (PKP3).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Plakophilin-3 (PKP3).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Plakophilin-3 (PKP3).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Plakophilin-3 (PKP3).	[14]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Plakophilin-3 (PKP3).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Plakophilin-3 (PKP3).	[16]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Plakophilin-3 (PKP3).	[17]

References

• [1] Up-regulation of plakophilin-2 and Down-regulation of plakophilin-3 are correlated with invasiveness in bladder cancer.Urology. 2012 Jan;79(1):240.e1-8. doi: 10.1016/j.urology.2011.08.049. Epub 2011 Nov 25.
• [2] An alternative promoter of the human plakophilin-3 gene controls the expression of the new isoform PKP3b.Cell Tissue Res. 2014 Jan;355(1):143-62. doi: 10.1007/s00441-013-1736-1. Epub 2013 Nov 1.
• [3] PKP3 interactions with MAPK-JNK-ERK1/2-mTOR pathway regulates autophagy and invasion in ovarian cancer.Biochem Biophys Res Commun. 2019 Jan 8;508(2):646-653. doi: 10.1016/j.bbrc.2018.11.163. Epub 2018 Dec 4.
• [4] Plakophilin3 loss leads to an increase in lipocalin2 expression, which is required for tumour formation.Exp Cell Res. 2018 Aug 15;369(2):251-265. doi: 10.1016/j.yexcr.2018.05.026. Epub 2018 May 24.
• [5] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [6] Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants.PLoS One. 2016 Feb 12;11(2):e0148649. doi: 10.1371/journal.pone.0148649. eCollection 2016.
• [7] Pemphigus vulgaris autoimmune globulin induces Src-dependent tyrosine-phosphorylation of plakophilin 3 and its detachment from desmoglein 3.Autoimmunity. 2014 Mar;47(2):134-40. doi: 10.3109/08916934.2013.866100. Epub 2013 Dec 16.
• [8] Plakophilin 3 oncogene as prognostic marker and therapeutic target for lung cancer.Cancer Res. 2005 Aug 15;65(16):7102-10. doi: 10.1158/0008-5472.CAN-04-1877.
• [9] Bioinformatics approach to mRNA markers discovery for detection of circulating tumor cells in patients with gastrointestinal cancer.Cancer Detect Prev. 2008;32(3):236-50. doi: 10.1016/j.cdp.2008.08.002. Epub 2008 Sep 17.
• [10] Expression of plakophilin 3 in diffuse malignant pleural mesothelioma.Histol Histopathol. 2018 Sep;33(9):995-1004. doi: 10.14670/HH-11-996. Epub 2018 May 3.
• [11] Dinitrosopiperazine-decreased PKP3 through upregulating miR-149 participates in nasopharyngeal carcinoma metastasis.Mol Carcinog. 2018 Dec;57(12):1763-1779. doi: 10.1002/mc.22895. Epub 2018 Sep 19.
• [12] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [18] 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.
• [19] 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.
• [20] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.
• [21] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.