Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUNV3CK)

• DOT Name: Leupaxin (LPXN)
• Gene Name: LPXN
• Related Disease:
  Prostate cancer
  Advanced cancer
  Bladder cancer
  Cushing disease
  Hepatocellular carcinoma
  leukaemia
  Leukemia
  Metastatic prostate carcinoma
  Neoplasm
  Prostate carcinoma
  Prostate neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
  Acute myelogenous leukaemia
  Adult lymphoma
  Breast cancer
  Breast carcinoma
  Carcinoma
  Ductal breast carcinoma in situ
  Endometrial cancer
  Endometrial carcinoma
  Lung cancer
  Lung carcinoma
  Lymphoma
  Pediatric lymphoma
  Adenocarcinoma
  Inflammatory bowel disease
  Metastatic malignant neoplasm
• UniProt ID: LPXN_HUMAN
• PDB ID: 1X3H; 4XEF; 4XEK; 4XEV
• Pfam ID: PF00412
• Sequence:
  MEELDALLEELERSTLQDSDEYSNPAPLPLDQHSRKETNLDETSEILSIQDNTSPLPAQL
  VYTTNIQELNVYSEAQEPKESPPPSKTSAAAQLDELMAHLTEMQAKVAVRADAGKKHLPD
  KQDHKASLDSMLGGLEQELQDLGIATVPKGHCASCQKPIAGKVIHALGQSWHPEHFVCTH
  CKEEIGSSPFFERSGLAYCPNDYHQLFSPRCAYCAAPILDKVLTAMNQTWHPEHFFCSHC
  GEVFGAEGFHEKDKKPYCRKDFLAMFSPKCGGCNRPVLENYLSAMDTVWHPECFVCGDCF
  TSFSTGSFFELDGRPFCELHYHHRRGTLCHGCGQPITGRCISAMGYKFHPEHFVCAFCLT
  QLSKGIFREQNDKTYCQPCFNKLFPL
• Function: Transcriptional coactivator for androgen receptor (AR) and serum response factor (SRF). Contributes to the regulation of cell adhesion, spreading and cell migration and acts as a negative regulator in integrin-mediated cell adhesion events. Suppresses the integrin-induced tyrosine phosphorylation of paxillin (PXN). May play a critical role as an adapter protein in the formation of the adhesion zone in osteoclasts. Negatively regulates B-cell antigen receptor (BCR) signaling.
• Tissue Specificity: Macrophages, monocytes and osteoclasts (at protein level). Strongly expressed in cells and tissues of hematopoietic origin. Highest expression in lymphoid tissues such as spleen, lymph node, thymus and appendix and in the vascular smooth muscle. Lower levels in bone marrow and fetal liver. Also expressed in peripheral blood lymphocytes and a number of hematopoietic cell lines. Very low levels found in epithelial cell lines. Expressed in prostate cancer (PCa) cells and its expression intensity is directly linked to PCa progression.

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Posttranslational Modification	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[2]
Cushing disease	DISOG6P2	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
leukaemia	DISS7D1V	Strong	Biomarker	[5]
Leukemia	DISNAKFL	Strong	Biomarker	[5]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Genetic Variation	[5]
Adult lymphoma	DISK8IZR	Disputed	Altered Expression	[7]
Breast cancer	DIS7DPX1	Disputed	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Disputed	Altered Expression	[8]
Carcinoma	DISH9F1N	Disputed	Biomarker	[8]
Ductal breast carcinoma in situ	DISLCJY7	Disputed	Altered Expression	[8]
Endometrial cancer	DISW0LMR	Disputed	Altered Expression	[8]
Endometrial carcinoma	DISXR5CY	Disputed	Altered Expression	[8]
Lung cancer	DISCM4YA	Disputed	Altered Expression	[8]
Lung carcinoma	DISTR26C	Disputed	Altered Expression	[8]
Lymphoma	DISN6V4S	Disputed	Altered Expression	[7]
Pediatric lymphoma	DIS51BK2	Disputed	Altered Expression	[7]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[9]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[10]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Leupaxin (LPXN) affects the response to substance of Fluorouracil.	[30]

19 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 Leupaxin (LPXN).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Leupaxin (LPXN).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Leupaxin (LPXN).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Leupaxin (LPXN).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Leupaxin (LPXN).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Leupaxin (LPXN).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Leupaxin (LPXN).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Leupaxin (LPXN).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Leupaxin (LPXN).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Leupaxin (LPXN).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Leupaxin (LPXN).	[21]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Leupaxin (LPXN).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Leupaxin (LPXN).	[23]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Leupaxin (LPXN).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Leupaxin (LPXN).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Leupaxin (LPXN).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Leupaxin (LPXN).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Leupaxin (LPXN).	[28]
Resorcinol	DMM37C0	Investigative	Resorcinol decreases the expression of Leupaxin (LPXN).	[29]

1 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 increases the methylation of Leupaxin (LPXN).	[25]

References

• [1] Leupaxin stimulates adhesion and migration of prostate cancer cells through modulation of the phosphorylation status of the actin-binding protein caldesmon.Oncotarget. 2015 May 30;6(15):13591-606. doi: 10.18632/oncotarget.3792.
• [2] Leupaxin Promotes Bladder Cancer Proliferation, Metastasis, and Angiogenesis Through the PI3K/AKT Pathway.Cell Physiol Biochem. 2018;47(6):2250-2260. doi: 10.1159/000491536. Epub 2018 Jul 5.
• [3] Lipoprotein particles in patients with pediatric Cushing disease and possible cardiovascular risks.Pediatr Res. 2019 Sep;86(3):375-381. doi: 10.1038/s41390-019-0438-0. Epub 2019 May 21.
• [4] Regulation of -catenin transcription activity by leupaxin in hepatocellular carcinoma.Tumour Biol. 2016 Feb;37(2):2313-20. doi: 10.1007/s13277-015-4060-4. Epub 2015 Sep 11.
• [5] ETV6-LPXN fusion transcript generated by t(11;12)(q12.1;p13) in a patient with relapsing acute myeloid leukemia with NUP98-HOXA9.Genes Chromosomes Cancer. 2016 Mar;55(3):242-50. doi: 10.1002/gcc.22327. Epub 2015 Nov 6.
• [6] Interaction of Pyk2 and PTP-PEST with leupaxin in prostate cancer cells.Am J Physiol Cell Physiol. 2007 Jun;292(6):C2288-96. doi: 10.1152/ajpcell.00503.2006. Epub 2007 Feb 28.
• [7] Splenic marginal zone lymphoma: proposal of new diagnostic and prognostic markers identified after tissue and cDNA microarray analysis.Blood. 2005 Sep 1;106(5):1831-8. doi: 10.1182/blood-2004-10-3898. Epub 2005 May 24.
• [8] Leupaxin is expressed in mammary carcinoma and acts as a transcriptional activator of the estrogen receptor .Int J Oncol. 2015 Jul;47(1):106-14. doi: 10.3892/ijo.2015.2988. Epub 2015 May 6.
• [9] Leupaxin acts as a mediator in prostate carcinoma progression through deregulation of p120catenin expression.Oncogene. 2009 Nov 12;28(45):3971-82. doi: 10.1038/onc.2009.254. Epub 2009 Aug 24.
• [10] Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012 Nov 1;491(7422):119-24. doi: 10.1038/nature11582.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] 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.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [20] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [23] 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.
• [24] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.
• [29] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [30] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.