Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT19CT2Z)

• DOT Name: Serine/threonine-protein kinase PLK3 (PLK3)
• Synonyms: EC 2.7.11.21; Cytokine-inducible serine/threonine-protein kinase; FGF-inducible kinase; Polo-like kinase 3; PLK-3; Proliferation-related kinase
• Gene Name: PLK3
• Related Disease:
  Carcinoma
  Head and neck cancer
  Head and neck carcinoma
  Advanced cancer
  Alopecia
  Breast cancer
  Breast carcinoma
  Burkitt lymphoma
  Cholangiocarcinoma
  Colorectal carcinoma
  Congenital contractural arachnodactyly
  Epilepsy
  Gastric cancer
  Keratoconus
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Myopia
  Neoplasm
  Prion disease
  Prostate cancer
  Prostate carcinoma
  Refractive error
  Retinoblastoma
  Stomach cancer
  Metastatic malignant neoplasm
  Squamous cell anal carcinoma
  Rheumatoid arthritis
  Lymphoma
  Osteoporosis
• UniProt ID: PLK3_HUMAN
• PDB ID: 4B6L
• EC Number: 2.7.11.21
• Pfam ID: PF00069 ; PF00659
• Sequence:
  MEPAAGFLSPRPFQRAAAAPAPPAGPGPPPSALRGPELEMLAGLPTSDPGRLITDPRSGR
  TYLKGRLLGKGGFARCYEATDTETGSAYAVKVIPQSRVAKPHQREKILNEIELHRDLQHR
  HIVRFSHHFEDADNIYIFLELCSRKSLAHIWKARHTLLEPEVRYYLRQILSGLKYLHQRG
  ILHRDLKLGNFFITENMELKVGDFGLAARLEPPEQRKKTICGTPNYVAPEVLLRQGHGPE
  ADVWSLGCVMYTLLCGSPPFETADLKETYRCIKQVHYTLPASLSLPARQLLAAILRASPR
  DRPSIDQILRHDFFTKGYTPDRLPISSCVTVPDLTPPNPARSLFAKVTKSLFGRKKKSKN
  HAQERDEVSGLVSGLMRTSVGHQDARPEAPAASGPAPVSLVETAPEDSSPRGTLASSGDG
  FEEGLTVATVVESALCALRNCIAFMPPAEQNPAPLAQPEPLVWVSKWVDYSNKFGFGYQL
  SSRRVAVLFNDGTHMALSANRKTVHYNPTSTKHFSFSVGAVPRALQPQLGILRYFASYME
  QHLMKGGDLPSVEEVEVPAPPLLLQWVKTDQALLMLFSDGTVQVNFYGDHTKLILSGWEP
  LLVTFVARNRSACTYLASHLRQLGCSPDLRQRLRYALRLLRDRSPA
• Function: Serine/threonine-protein kinase involved in cell cycle regulation, response to stress and Golgi disassembly. Polo-like kinases act by binding and phosphorylating proteins that are already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates ATF2, BCL2L1, CDC25A, CDC25C, CHEK2, HIF1A, JUN, p53/TP53, p73/TP73, PTEN, TOP2A and VRK1. Involved in cell cycle regulation: required for entry into S phase and cytokinesis. Phosphorylates BCL2L1, leading to regulate the G2 checkpoint and progression to cytokinesis during mitosis. Plays a key role in response to stress: rapidly activated upon stress stimulation, such as ionizing radiation, reactive oxygen species (ROS), hyperosmotic stress, UV irradiation and hypoxia. Involved in DNA damage response and G1/S transition checkpoint by phosphorylating CDC25A, p53/TP53 and p73/TP73. Phosphorylates p53/TP53 in response to reactive oxygen species (ROS), thereby promoting p53/TP53-mediated apoptosis. Phosphorylates CHEK2 in response to DNA damage, promoting the G2/M transition checkpoint. Phosphorylates the transcription factor p73/TP73 in response to DNA damage, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates HIF1A and JUN is response to hypoxia. Phosphorylates ATF2 following hyperosmotic stress in corneal epithelium. Also involved in Golgi disassembly during the cell cycle: part of a MEK1/MAP2K1-dependent pathway that induces Golgi fragmentation during mitosis by mediating phosphorylation of VRK1. May participate in endomitotic cell cycle, a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation, via its interaction with CIB1.
• Tissue Specificity: Transcripts are highly detected in placenta, lung, followed by skeletal muscle, heart, pancreas, ovaries and kidney and weakly detected in liver and brain. May have a short half-live. In cells of hematopoietic origin, strongly and exclusively detected in terminally differentiated macrophages. Transcript expression appears to be down-regulated in primary lung tumor.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Tuberculosis (hsa05152)
• Reactome Pathway:
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain (R-HSA-6804115)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma	DISH9F1N	Definitive	Altered Expression	[1]
Head and neck cancer	DISBPSQZ	Definitive	Altered Expression	[1]
Head and neck carcinoma	DISOU1DS	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alopecia	DIS37HU4	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[5]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Altered Expression	[6]
Epilepsy	DISBB28L	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Keratoconus	DISOONXH	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Altered Expression	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[10]
Myopia	DISK5S60	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Prion disease	DISOUMB0	Strong	Biomarker	[13]
Prostate cancer	DISF190Y	Strong	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[14]
Refractive error	DISWNEQ1	Strong	Biomarker	[15]
Retinoblastoma	DISVPNPB	Strong	Altered Expression	[16]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[17]
Squamous cell anal carcinoma	DISTY5YZ	moderate	Posttranslational Modification	[17]
Rheumatoid arthritis	DISTSB4J	Disputed	Biomarker	[18]
Lymphoma	DISN6V4S	Limited	Posttranslational Modification	[19]
Osteoporosis	DISF2JE0	Limited	Genetic Variation	[20]

2 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 Serine/threonine-protein kinase PLK3 (PLK3).	[21]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Serine/threonine-protein kinase PLK3 (PLK3).	[33]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[25]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[26]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[27]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[29]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[30]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[31]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[29]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[32]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[34]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[35]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[36]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[37]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[38]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[39]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[40]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[39]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[36]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[41]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[41]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[36]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[42]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[43]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[44]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[45]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[46]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[47]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[48]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Serine/threonine-protein kinase PLK3 (PLK3).	[49]

References

• [1] PRK, a cell cycle gene localized to 8p21, is downregulated in head and neck cancer.Genes Chromosomes Cancer. 2000 Mar;27(3):332-6. doi: 10.1002/(sici)1098-2264(200003)27:3<332::aid-gcc15>3.0.co;2-k.
• [2] Polo-like kinase 3 inhibits glucose metabolism in colorectal cancer by targeting HSP90/STAT3/HK2 signaling.J Exp Clin Cancer Res. 2019 Oct 26;38(1):426. doi: 10.1186/s13046-019-1418-2.
• [3] Prevention of chemotherapy-induced alopecia by the anti-death FNK protein.Life Sci. 2008 Jan 16;82(3-4):218-25. doi: 10.1016/j.lfs.2007.11.011. Epub 2007 Dec 3.
• [4] Calcium-dependent inhibition of polo-like kinase 3 activity by CIB1 in breast cancer cells.Int J Cancer. 2011 Feb 1;128(3):587-96. doi: 10.1002/ijc.25388.
• [5] Transcriptional silencing of Polo-like kinase 2 (SNK/PLK2) is a frequent event in B-cell malignancies.Blood. 2006 Jan 1;107(1):250-6. doi: 10.1182/blood-2005-03-1194. Epub 2005 Sep 13.
• [6] Polo-like kinase 3 is associated with improved overall survival in cholangiocarcinoma.Liver Int. 2015 Nov;35(11):2448-57. doi: 10.1111/liv.12839. Epub 2015 Apr 10.
• [7] Long-term antiepileptic effects of chronic intake of CNK-602A, a thyrotropin-releasing hormone analogue, on spontaneously epileptic rats.Epilepsia. 1996 Apr;37(4):328-31. doi: 10.1111/j.1528-1157.1996.tb00567.x.
• [8] Long noncoding RNA HOXA-AS2 promotes gastric cancer proliferation by epigenetically silencing P21/PLK3/DDIT3 expression.Oncotarget. 2015 Oct 20;6(32):33587-601. doi: 10.18632/oncotarget.5599.
• [9] Ten-Year Outcomes of Progressive Keratoconus Management With the Athens Protocol (Topography-Guided Partial-Refraction PRK Combined With CXL).J Refract Surg. 2019 Aug 1;35(8):478-483. doi: 10.3928/1081597X-20190627-01.
• [10] Intron/exon organization and polymorphisms of the PLK3/PRK gene in human lung carcinoma cell lines.Genes Chromosomes Cancer. 2001 Dec;32(4):384-9. doi: 10.1002/gcc.1204.
• [11] Mitomycin C 0.02 and 0.002% efficacy in preventing haze after photorefractive keratectomy.Int Ophthalmol. 2019 Feb;39(2):341-345. doi: 10.1007/s10792-017-0817-7. Epub 2018 Jan 16.
• [12] Association of Polo-Like Kinase 3 and PhosphoT273 Caspase 8 Levels With Disease-Related Outcomes Among Cervical Squamous Cell Carcinoma Patients Treated With Chemoradiation and Brachytherapy.Front Oncol. 2019 Aug 14;9:742. doi: 10.3389/fonc.2019.00742. eCollection 2019.
• [13] Overexpression of PLK3 Mediates the Degradation of Abnormal Prion Proteins Dependent on Chaperone-Mediated Autophagy.Mol Neurobiol. 2017 Aug;54(6):4401-4413. doi: 10.1007/s12035-016-9985-0. Epub 2016 Jun 25.
• [14] Polo-like kinase 3 is associated with poor prognosis and regulates proliferation and metastasis in prostate cancer.Cancer Manag Res. 2019 Feb 14;11:1517-1524. doi: 10.2147/CMAR.S176762. eCollection 2019.
• [15] Surgical Options for the Refractive Correction of Keratoconus: Myth or Reality.J Ophthalmol. 2017;2017:7589816. doi: 10.1155/2017/7589816. Epub 2017 Dec 18.
• [16] The retinoblastoma tumor suppressor modulates DNA repair and radioresponsiveness.Clin Cancer Res. 2014 Nov 1;20(21):5468-5482. doi: 10.1158/1078-0432.CCR-14-0326. Epub 2014 Aug 27.
• [17] Polo-like kinase 3 and phosphoT273 caspase-8 are associated with improved local tumor control and survival in patients with anal carcinoma treated with concomitant chemoradiotherapy.Oncotarget. 2016 Aug 16;7(33):53339-53349. doi: 10.18632/oncotarget.10801.
• [18] Identification of novel genetic loci for osteoporosis and/or rheumatoid arthritis using cFDR approach.PLoS One. 2017 Aug 30;12(8):e0183842. doi: 10.1371/journal.pone.0183842. eCollection 2017.
• [19] Epigenetic inactivation implies a tumor suppressor function in hematologic malignancies for Polo-like kinase 2 but not Polo-like kinase 3.Cell Cycle. 2006 Jun;5(12):1262-4. doi: 10.4161/cc.5.12.2813.
• [20] Age at menarche and osteoporosis: A Mendelian randomization study.Bone. 2018 Dec;117:91-97. doi: 10.1016/j.bone.2018.09.015. Epub 2018 Sep 18.
• [21] 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.
• [22] 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.
• [23] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [24] 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.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [27] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [32] Regulation of p53 stability and function in HCT116 colon cancer cells. J Biol Chem. 2004 Feb 27;279(9):7598-605. doi: 10.1074/jbc.M311732200. Epub 2003 Dec 9.
• [33] 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.
• [34] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [35] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [36] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [37] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [38] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [39] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [40] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [41] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [42] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [43] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [44] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [45] 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.
• [46] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [47] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [48] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [49] 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.