Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHI7TA0)

• DOT Name: Laminin subunit alpha-4 (LAMA4)
• Synonyms: Laminin-14 subunit alpha; Laminin-8 subunit alpha; Laminin-9 subunit alpha
• Gene Name: LAMA4
• Related Disease:
  Brain neoplasm
  Dilated cardiomyopathy 1JJ
  Familial dilated cardiomyopathy
  Hamartoma
  Hepatocellular carcinoma
  Multiple sclerosis
  Triple negative breast cancer
  Carcinoma
  Clear cell renal carcinoma
  Fetal growth restriction
  Gastric cancer
  Stomach cancer
  Obsolete familial isolated dilated cardiomyopathy
  Asthma
  Dilated cardiomyopathy
  Glaucoma/ocular hypertension
  Glioma
  Grade II glioma
  Metastatic malignant neoplasm
  Neoplasm
  Renal cell carcinoma
• UniProt ID: LAMA4_HUMAN
• Pfam ID: PF00053 ; PF02210 ; PF06008 ; PF06009
• Sequence:
  MALSSAWRSVLPLWLLWSAACSRAASGDDNAFPFDIEGSSAVGRQDPPETSEPRVALGRL
  PPAAEKCNAGFFHTLSGECVPCDCNGNSNECLDGSGYCVHCQRNTTGEHCEKCLDGYIGD
  SIRGAPQFCQPCPCPLPHLANFAESCYRKNGAVRCICNENYAGPNCERCAPGYYGNPLLI
  GSTCKKCDCSGNSDPNLIFEDCDEVTGQCRNCLRNTTGFKCERCAPGYYGDARIAKNCAV
  CNCGGGPCDSVTGECLEEGFEPPTGMDCPTISCDKCVWDLTDALRLAALSIEEGKSGVLS
  VSSGAAAHRHVNEINATIYLLKTKLSERENQYALRKIQINNAENTMKSLLSDVEELVEKE
  NQASRKGQLVQKESMDTINHASQLVEQAHDMRDKIQEINNKMLYYGEEHELSPKEISEKL
  VLAQKMLEEIRSRQPFFTQRELVDEEADEAYELLSQAESWQRLHNETRTLFPVVLEQLDD
  YNAKLSDLQEALDQALNYVRDAEDMNRATAARQRDHEKQQERVREQMEVVNMSLSTSADS
  LTTPRLTLSELDDIIKNASGIYAEIDGAKSELQVKLSNLSNLSHDLVQEAIDHAQDLQQE
  ANELSRKLHSSDMNGLVQKALDASNVYENIVNYVSEANETAEFALNTTDRIYDAVSGIDT
  QIIYHKDESENLLNQARELQAKAESSSDEAVADTSRRVGGALARKSALKTRLSDAVKQLQ
  AAERGDAQQRLGQSRLITEEANRTTMEVQQATAPMANNLTNWSQNLQHFDSSAYNTAVNS
  ARDAVRNLTEVVPQLLDQLRTVEQKRPASNVSASIQRIRELIAQTRSVASKIQVSMMFDG
  QSAVEVHSRTSMDDLKAFTSLSLYMKPPVKRPELTETADQFILYLGSKNAKKEYMGLAIK
  NDNLVYVYNLGTKDVEIPLDSKPVSSWPAYFSIVKIERVGKHGKVFLTVPSLSSTAEEKF
  IKKGEFSGDDSLLDLDPEDTVFYVGGVPSNFKLPTSLNLPGFVGCLELATLNNDVISLYN
  FKHIYNMDPSTSVPCARDKLAFTQSRAASYFFDGSGYAVVRDITRRGKFGQVTRFDIEVR
  TPADNGLILLMVNGSMFFRLEMRNGYLHVFYDFGFSGGPVHLEDTLKKAQINDAKYHEIS
  IIYHNDKKMILVVDRRHVKSMDNEKMKIPFTDIYIGGAPPEILQSRALRAHLPLDINFRG
  CMKGFQFQKKDFNLLEQTETLGVGYGCPEDSLISRRAYFNGQSFIASIQKISFFDGFEGG
  FNFRTLQPNGLLFYYASGSDVFSISLDNGTVIMDVKGIKVQSVDKQYNDGLSHFVISSVS
  PTRYELIVDKSRVGSKNPTKGKIEQTQASEKKFYFGGSPISAQYANFTGCISNAYFTRVD
  RDVEVEDFQRYTEKVHTSLYECPIESSPLFLLHKKGKNLSKPKASQNKKGGKSKDAPSWD
  PVALKLPERNTPRNSHCHLSNSPRAIEHAYQYGGTANSRQEFEHLKGDFGAKSQFSIRLR
  TRSSHGMIFYVSDQEENDFMTLFLAHGRLVYMFNVGHKKLKIRSQEKYNDGLWHDVIFIR
  ERSSGRLVIDGLRVLEESLPPTEATWKIKGPIYLGGVAPGKAVKNVQINSIYSFSGCLSN
  LQLNGASITSASQTFSVTPCFEGPMETGTYFSTEGGYVVLDESFNIGLKFEIAFEVRPRS
  SSGTLVHGHSVNGEYLNVHMKNGQVIVKVNNGIRDFSTSVTPKQSLCDGRWHRITVIRDS
  NVVQLDVDSEVNHVVGPLNPKPIDHREPVFVGGVPESLLTPRLAPSKPFTGCIRHFVIDG
  HPVSFSKAALVSGAVSINSCPAA
• Function: Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
• Tissue Specificity: Detected in placenta (at protein level) . Detected in fibroblasts and urine (at protein level) . In adult, strong expression in heart, lung, ovary small and large intestines, placenta, liver; weak or no expression in skeletal muscle, kidney, pancreas, testis, prostate, brain. High expression in fetal lung and kidney. Expression in fetal and newborn tissues is observed in certain mesenchymal cells in tissues such as smooth muscle and dermis.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  African trypanosomiasis (hsa05143)
  Toxoplasmosis (hsa05145)
  Amoebiasis (hsa05146)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  Non-integrin membrane-ECM interactions (R-HSA-3000171)
  ECM proteoglycans (R-HSA-3000178)
  MET activates PTK2 signaling (R-HSA-8874081)
  Laminin interactions (R-HSA-3000157)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Brain neoplasm	DISY3EKS	Strong	Biomarker	[1]
Dilated cardiomyopathy 1JJ	DISN7E8S	Strong	Autosomal dominant	[2]
Familial dilated cardiomyopathy	DISBHDU9	Strong	GermlineCausalMutation	[2]
Hamartoma	DIS0I87H	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[5]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	moderate	Altered Expression	[7]
Clear cell renal carcinoma	DISBXRFJ	moderate	Biomarker	[8]
Fetal growth restriction	DIS5WEJ5	moderate	Biomarker	[9]
Gastric cancer	DISXGOUK	moderate	Biomarker	[10]
Stomach cancer	DISKIJSX	moderate	Biomarker	[10]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[2]
Asthma	DISW9QNS	Disputed	Biomarker	[11]
Dilated cardiomyopathy	DISX608J	Limited	Autosomal dominant	[12]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Altered Expression	[13]
Glioma	DIS5RPEH	Limited	Altered Expression	[14]
Grade II glioma	DIS9NNT0	Limited	Altered Expression	[15]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[8]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[16]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
NAPQI	DM8F5LR	Investigative	Laminin subunit alpha-4 (LAMA4) affects the response to substance of NAPQI.	[40]

25 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 Laminin subunit alpha-4 (LAMA4).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Laminin subunit alpha-4 (LAMA4).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Laminin subunit alpha-4 (LAMA4).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Laminin subunit alpha-4 (LAMA4).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Laminin subunit alpha-4 (LAMA4).	[21]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Laminin subunit alpha-4 (LAMA4).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Laminin subunit alpha-4 (LAMA4).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Laminin subunit alpha-4 (LAMA4).	[24]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Laminin subunit alpha-4 (LAMA4).	[25]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Laminin subunit alpha-4 (LAMA4).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Laminin subunit alpha-4 (LAMA4).	[27]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Laminin subunit alpha-4 (LAMA4).	[28]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Laminin subunit alpha-4 (LAMA4).	[29]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Laminin subunit alpha-4 (LAMA4).	[25]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Laminin subunit alpha-4 (LAMA4).	[30]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Laminin subunit alpha-4 (LAMA4).	[31]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Laminin subunit alpha-4 (LAMA4).	[32]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Laminin subunit alpha-4 (LAMA4).	[33]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Laminin subunit alpha-4 (LAMA4).	[32]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Laminin subunit alpha-4 (LAMA4).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Laminin subunit alpha-4 (LAMA4).	[35]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Laminin subunit alpha-4 (LAMA4).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Laminin subunit alpha-4 (LAMA4).	[37]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Laminin subunit alpha-4 (LAMA4).	[38]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Laminin subunit alpha-4 (LAMA4).	[39]

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 Laminin subunit alpha-4 (LAMA4).	[34]

References

• [1] Changes in laminin isoforms associated with brain tumor invasion and angiogenesis.Front Biosci. 2006 Jan 1;11:81-8. doi: 10.2741/1781.
• [2] Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells. Circulation. 2007 Jul 31;116(5):515-25. doi: 10.1161/CIRCULATIONAHA.107.689984. Epub 2007 Jul 23.
• [3] HMGI(Y) activation by chromosome 6p21 rearrangements in multilineage mesenchymal cells from pulmonary hamartoma.Am J Pathol. 1997 Mar;150(3):901-10.
• [4] LAMA4, highly expressed in human hepatocellular carcinoma from Chinese patients, is a novel marker of tumor invasion and metastasis.J Cancer Res Clin Oncol. 2008 Jun;134(6):705-14. doi: 10.1007/s00432-007-0342-6. Epub 2007 Dec 14.
• [5] Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus.J Neuroinflammation. 2018 Aug 22;15(1):236. doi: 10.1186/s12974-018-1276-4.
• [6] MiR-539 inhibits proliferation and migration of triple-negative breast cancer cells by down-regulating LAMA4 expression.Cancer Cell Int. 2018 Jan 30;18:16. doi: 10.1186/s12935-018-0512-4. eCollection 2018.
• [7] Identification of molecular determinants of primary and metastatic tumour re-initiation in breast cancer.Nat Cell Biol. 2015 May;17(5):651-64. doi: 10.1038/ncb3148. Epub 2015 Apr 13.
• [8] MicroRNA-200b is downregulated and suppresses metastasis by targeting LAMA4 in renal cell carcinoma.EBioMedicine. 2019 Jun;44:439-451. doi: 10.1016/j.ebiom.2019.05.041. Epub 2019 May 23.
• [9] Intrauterine growth restriction decreases NF-B signaling in fetal pulmonary artery endothelial cells of fetal sheep.Am J Physiol Lung Cell Mol Physiol. 2018 Sep 1;315(3):L348-L359. doi: 10.1152/ajplung.00052.2018. Epub 2018 May 3.
• [10] LAMA4 expression is activated by zinc finger Eboxbinding homeobox1 and independently predicts poor overall survival in gastric cancer.Oncol Rep. 2018 Sep;40(3):1725-1733. doi: 10.3892/or.2018.6564. Epub 2018 Jul 12.
• [11] Laminin 4 contributes to airway remodeling and inflammation in asthma.Am J Physiol Lung Cell Mol Physiol. 2019 Dec 1;317(6):L768-L777. doi: 10.1152/ajplung.00222.2019. Epub 2019 Sep 25.
• [12] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [13] Down-regulated LAMA4 inhibits oxidative stress-induced apoptosis of retinal ganglion cells through the MAPK signaling pathway in rats with glaucoma.Cell Cycle. 2019 May;18(9):932-948. doi: 10.1080/15384101.2019.1593645. Epub 2019 Apr 19.
• [14] Downregulation of laminin alpha4 chain expression inhibits glioma invasion in vitro and in vivo.Int J Cancer. 2005 Oct 20;117(1):41-50. doi: 10.1002/ijc.21102.
• [15] IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas.Neuro Oncol. 2018 Oct 9;20(11):1505-1516. doi: 10.1093/neuonc/noy088.
• [16] Perioperative, Spatiotemporally Coordinated Activation of T and NK Cells Prevents Recurrence of Pancreatic Cancer.Cancer Res. 2018 Jan 15;78(2):475-488. doi: 10.1158/0008-5472.CAN-17-2415. Epub 2017 Nov 27.
• [17] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [18] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [19] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [20] 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.
• [21] 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.
• [22] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [27] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [28] Dose- and time-dependent effects of phenobarbital on gene expression profiling in human hepatoma HepaRG cells. Toxicol Appl Pharmacol. 2009 Feb 1;234(3):345-60.
• [29] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [30] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [31] MMP-14 and TIMP-2 overexpression protects against hydroquinone-induced oxidant injury in RPE: implications for extracellular matrix turnover. Invest Ophthalmol Vis Sci. 2007 Dec;48(12):5662-70. doi: 10.1167/iovs.07-0392.
• [32] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [33] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [34] 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.
• [35] 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.
• [36] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [37] 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.
• [38] 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.
• [39] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [40] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.