Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXHT4JM)

• DOT Name: Kinesin-like protein KIF14 (KIF14)
• Gene Name: KIF14
• Related Disease:
  Adenocarcinoma
  Autosomal recessive primary microcephaly
  Lung carcinoma
  Squamous cell carcinoma
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Ciliopathy
  Epithelial ovarian cancer
  Fetal akinesia deformation sequence 1
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome
  Lung cancer
  Medulloblastoma
  Microcephaly 20, primary, autosomal recessive
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Pituitary stalk interruption syndrome
  Prostate cancer
  Prostate carcinoma
  Retinoblastoma
  Stomach cancer
  Triple negative breast cancer
  Adult glioblastoma
  Anaplastic astrocytoma
  Astrocytoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Intellectual disability
  Breast neoplasm
  Isolated congenital microcephaly
  Lung adenocarcinoma
  Lung neoplasm
  Meningioma
• UniProt ID: KIF14_HUMAN
• Pfam ID: PF00498 ; PF00225 ; PF16183
• Sequence:
  MSLHSTHNRNNSGDILDIPSSQNSSSLNALTHSSRLKLHLKSDMSECENDDPLLRSAGKV
  RDINRTYVISASRKTADMPLTPNPVGRLALQRRTTRNKESSLLVSELEDTTEKTAETRLT
  LQRRAKTDSAEKWKTAEIDSVKMTLNVGGETENNGVSKESRTNVRIVNNAKNSFVASSVP
  LDEDPQVIEMMADKKYKETFSAPSRANENVALKYSSNRPPIASLSQTEVVRSGHLTTKPT
  QSKLDIKVLGTGNLYHRSIGKEIAKTSNKFGSLEKRTPTKCTTEHKLTTKCSLPQLKSPA
  PSILKNRMSNLQVKQRPKSSFLANKQERSAENTILPEEETVVQNTSAGKDPLKVENSQVT
  VAVRVRPFTKREKIEKASQVVFMSGKEITVEHPDTKQVYNFIYDVSFWSFDECHPHYASQ
  TTVYEKLAAPLLERAFEGFNTCLFAYGQTGSGKSYTMMGFSEEPGIIPRFCEDLFSQVAR
  KQTQEVSYHIEMSFFEVYNEKIHDLLVCKDENGQRKQPLRVREHPVYGPYVEALSMNIVS
  SYADIQSWLELGNKQRATAATGMNDKSSRSHSVFTLVMTQTKTEFVEGEEHDHRITSRIN
  LIDLAGSERCSTAHTNGDRLKEGVSINKSLLTLGKVISALSEQANQRSVFIPYRESVLTW
  LLKESLGGNSKTAMIATISPAASNIEETLSTLRYANQARLIVNIAKVNEDMNAKLIRELK
  AEIAKLKAAQRNSRNIDPERYRLCRQEITSLRMKLHQQERDMAEMQRVWKEKFEQAEKRK
  LQETKELQKAGIMFQMDNHLPNLVNLNEDPQLSEMLLYMIKEGTTTVGKYKPNSSHDIQL
  SGVLIADDHCTIKNFGGTVSIIPVGEAKTYVNGKHILEITVLRHGDRVILGGDHYFRFNH
  PVEVQKGKRPSGRDTPISEGPKDFEFAKNELLMAQRSQLEAEIKEAQLKAKEEMMQGIQI
  AKEMAQQELSSQKAAYESKIKALEAELREESQRKKMQEINNQKANHKIEELEKAKQHLEQ
  EIYVNKKRLEMETLATKQALEDHSIRHARILEALETEKQKIAKEVQILQQNRNNRDKTFT
  VQTTWSSMKLSMMIQEANAISSKLKTYYVFGRHDISDKSSSDTSIRVRNLKLGISTFWSL
  EKFESKLAAMKELYESNGSNRGEDAFCDPEDEWEPDITDAPVSSLSRRRSRSLMKNRRIS
  GCLHDIQVHPIKNLHSSHSSGLMDKSSTIYSNSAESFLPGICKELIGSSLDFFGQSYDEE
  RTIADSLINSFLKIYNGLFAISKAHEEQDEESQDNLFSSDRAIQSLTIQTACAFEQLVVL
  MKHWLSDLLPCTNIARLEDELRQEVKKLGGYLQLFLQGCCLDISSMIKEAQKNAIQIVQQ
  AVKYVGQLAVLKGSKLHFLENGNNKAASVQEEFMDAVCDGVGLGMKILLDSGLEKAKELQ
  HELFRQCTKNEVTKEMKTNAMGLIRSLENIFAESKIKSFRRQVQEENFEYQDFKRMVNRA
  PEFLKLKHCLEKAIEIIISALKGCHSDINLLQTCVESIRNLASDFYSDFSVPSTSVGSYE
  SRVTHIVHQELESLAKSLLFCFESEESPDLLKPWETYNQNTKEEHQQSKSSGIDGSKNKG
  VPKRVYELHGSSPAVSSEECTPSRIQWV
• Function: Microtubule motor protein that binds to microtubules with high affinity through each tubulin heterodimer and has an ATPase activity. Plays a role in many processes like cell division, cytokinesis and also in cell proliferation and apoptosis. During cytokinesis, targets to central spindle and midbody through its interaction with PRC1 and CIT respectively. Regulates cell growth through regulation of cell cycle progression and cytokinesis. During cell cycle progression acts through SCF-dependent proteasomal ubiquitin-dependent protein catabolic process which controls CDKN1B degradation, resulting in positive regulation of cyclins, including CCNE1, CCND1 and CCNB1. During late neurogenesis, regulates the cerebellar, cerebral cortex and olfactory bulb development through regulation of apoptosis, cell proliferation and cell division. Also is required for chromosome congression and alignment during mitotic cell cycle process. Regulates cell spreading, focal adhesion dynamics, and cell migration through its interaction with RADIL resulting in regulation of RAP1A-mediated inside-out integrin activation by tethering RADIL on microtubules.
• KEGG Pathway: Motor proteins (hsa04814)
• Reactome Pathway:
  RND2 GTPase cycle (R-HSA-9696270)
  RND1 GTPase cycle (R-HSA-9696273)
  RHO GTPases activate CIT (R-HSA-5625900)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Altered Expression	[1]
Autosomal recessive primary microcephaly	DIS29IE3	Definitive	Autosomal recessive	[2]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[3]
Squamous cell carcinoma	DISQVIFL	Definitive	Altered Expression	[3]
B-cell neoplasm	DISVY326	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[6]
Fetal akinesia deformation sequence 1	DISKDI9L	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Altered Expression	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome	DIS4IBS6	Strong	Autosomal recessive	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[13]
Microcephaly 20, primary, autosomal recessive	DISAVGIQ	Strong	Autosomal recessive	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[3]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[6]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[6]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[14]
Pituitary stalk interruption syndrome	DISGSN5T	Strong	Biomarker	[15]
Prostate cancer	DISF190Y	Strong	Altered Expression	[16]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[16]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Triple negative breast cancer	DISAMG6N	Strong	Posttranslational Modification	[5]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[17]
Anaplastic astrocytoma	DISSBE0K	moderate	Biomarker	[17]
Astrocytoma	DISL3V18	moderate	Biomarker	[17]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[18]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[17]
Intellectual disability	DISMBNXP	Disputed	Genetic Variation	[19]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[20]
Isolated congenital microcephaly	DISUXHZ6	Limited	Genetic Variation	[21]
Lung adenocarcinoma	DISD51WR	Limited	Altered Expression	[1]
Lung neoplasm	DISVARNB	Limited	Altered Expression	[3]
Meningioma	DISPT4TG	Limited	Altered Expression	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Docetaxel	DMDI269	Approved	Kinesin-like protein KIF14 (KIF14) decreases the response to substance of Docetaxel.	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Kinesin-like protein KIF14 (KIF14).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Kinesin-like protein KIF14 (KIF14).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Kinesin-like protein KIF14 (KIF14).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Kinesin-like protein KIF14 (KIF14).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kinesin-like protein KIF14 (KIF14).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Kinesin-like protein KIF14 (KIF14).	[28]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kinesin-like protein KIF14 (KIF14).	[29]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Kinesin-like protein KIF14 (KIF14).	[30]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Kinesin-like protein KIF14 (KIF14).	[31]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Kinesin-like protein KIF14 (KIF14).	[32]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Kinesin-like protein KIF14 (KIF14).	[32]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Kinesin-like protein KIF14 (KIF14).	[33]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Kinesin-like protein KIF14 (KIF14).	[34]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Kinesin-like protein KIF14 (KIF14).	[35]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Kinesin-like protein KIF14 (KIF14).	[36]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Kinesin-like protein KIF14 (KIF14).	[37]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Kinesin-like protein KIF14 (KIF14).	[38]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Kinesin-like protein KIF14 (KIF14).	[39]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Kinesin-like protein KIF14 (KIF14).	[40]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of Kinesin-like protein KIF14 (KIF14).	[41]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Kinesin-like protein KIF14 (KIF14).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Kinesin-like protein KIF14 (KIF14).	[42]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Kinesin-like protein KIF14 (KIF14).	[43]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kinesin-like protein KIF14 (KIF14).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Kinesin-like protein KIF14 (KIF14).	[45]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Kinesin-like protein KIF14 (KIF14).	[46]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Kinesin-like protein KIF14 (KIF14).	[47]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Kinesin-like protein KIF14 (KIF14).	[48]

References

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• [2] Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype. Clin Genet. 2014 Sep;86(3):220-8. doi: 10.1111/cge.12301. Epub 2013 Nov 18.
• [3] KIF14 messenger RNA expression is independently prognostic for outcome in lung cancer.Clin Cancer Res. 2007 Jun 1;13(11):3229-34. doi: 10.1158/1078-0432.CCR-07-0393.
• [4] Observations on spontaneous tumor formation in mice overexpressing mitotic kinesin Kif14.Sci Rep. 2018 Nov 1;8(1):16152. doi: 10.1038/s41598-018-34603-4.
• [5] KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer. Neoplasia. 2014 Mar;16(3):247-56, 256.e2. doi: 10.1016/j.neo.2014.03.008.
• [6] Clinical relevance of cytoskeleton associated proteins for ovarian cancer.J Cancer Res Clin Oncol. 2018 Nov;144(11):2195-2205. doi: 10.1007/s00432-018-2710-9. Epub 2018 Aug 9.
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• [9] Long non-coding RNA PAXIP1-AS1 facilitates cell invasion and angiogenesis of glioma by recruiting transcription factor ETS1 to upregulate KIF14 expression.J Exp Clin Cancer Res. 2019 Dec 10;38(1):486. doi: 10.1186/s13046-019-1474-7.
• [10] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [11] Kif14 mutation causes severe brain malformation and hypomyelination. PLoS One. 2013;8(1):e53490. doi: 10.1371/journal.pone.0053490. Epub 2013 Jan 4.
• [12] Kinesin family member 14: an independent prognostic marker and potential therapeutic target for ovarian cancer.Int J Cancer. 2012 Apr 15;130(8):1844-54. doi: 10.1002/ijc.26189. Epub 2011 Aug 5.
• [13] The kinesin KIF14 is overexpressed in medulloblastoma and downregulation of KIF14 suppressed tumor proliferation and induced apoptosis.Lab Invest. 2017 Aug;97(8):946-961. doi: 10.1038/labinvest.2017.48. Epub 2017 May 15.
• [14] Consensus transcriptome signature of perineural invasion in pancreatic carcinoma.Mol Cancer Ther. 2009 Jun;8(6):1494-504. doi: 10.1158/1535-7163.MCT-08-0755. Epub 2009 Jun 9.
• [15] Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients.J Clin Endocrinol Metab. 2018 Feb 1;103(2):415-428. doi: 10.1210/jc.2017-01660.
• [16] Overexpression of a novel candidate oncogene KIF14 correlates with tumor progression and poor prognosis in prostate cancer.Oncotarget. 2017 Jul 11;8(28):45459-45469. doi: 10.18632/oncotarget.17564.
• [17] Inhibition of KIF14 Suppresses Tumor Cell Growth and Promotes Apoptosis in Human Glioblastoma.Cell Physiol Biochem. 2015;37(5):1659-70. doi: 10.1159/000438532. Epub 2015 Nov 5.
• [18] The histone H3 lysine-27 demethylase UTX plays a critical role in colorectal cancer cell proliferation.Cancer Cell Int. 2019 May 22;19:144. doi: 10.1186/s12935-019-0841-y. eCollection 2019.
• [19] Biallelic variants in KIF14 cause intellectual disability with microcephaly.Eur J Hum Genet. 2018 Mar;26(3):330-339. doi: 10.1038/s41431-017-0088-9. Epub 2018 Jan 17.
• [20] High expression of KIF14 in retinoblastoma: association with older age at diagnosis.Invest Ophthalmol Vis Sci. 2007 Nov;48(11):4901-6. doi: 10.1167/iovs.07-0063.
• [21] Loss-of-function mutations in KIF14 cause severe microcephaly and kidney development defects in humans and zebrafish.Hum Mol Genet. 2019 Mar 1;28(5):778-795. doi: 10.1093/hmg/ddy381.
• [22] Identification of KIF11 As a Novel Target in Meningioma.Cancers (Basel). 2019 Apr 15;11(4):545. doi: 10.3390/cancers11040545.
• [23] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [24] 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.
• [25] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [26] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [27] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [28] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [29] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [30] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [31] 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.
• [32] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [33] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [34] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [35] New insights into the mechanisms underlying 5-fluorouracil-induced intestinal toxicity based on transcriptomic and metabolomic responses in human intestinal organoids. Arch Toxicol. 2021 Aug;95(8):2691-2718. doi: 10.1007/s00204-021-03092-2. Epub 2021 Jun 20.
• [36] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [37] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [38] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [39] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [40] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [41] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [42] 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.
• [43] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [44] 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.
• [45] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [46] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
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• [48] 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.
• [49] KIF14 promotes AKT phosphorylation and contributes to chemoresistance in triple-negative breast cancer. Neoplasia. 2014 Mar;16(3):247-56, 256.e2. doi: 10.1016/j.neo.2014.03.008.