Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU8ZDC4)

• DOT Name: LLGL scribble cell polarity complex component 2 (LLGL2)
• Synonyms: HGL; Lethal(2) giant larvae protein homolog 2
• Gene Name: LLGL2
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Esophageal cancer
  Gastric cancer
  Neoplasm
  Neoplasm of esophagus
  Stomach cancer
  High blood pressure
• UniProt ID: L2GL2_HUMAN
• PDB ID: 3WP0; 3WP1; 6N8P; 6N8Q; 6N8R; 6N8S
• Pfam ID: PF08366 ; PF00400
• Sequence:
  MRRFLRPGHDPVRERLKRDLFQFNKTVEHGFPHQPSALGYSPSLRILAIGTRSGAIKLYG
  APGVEFMGLHQENNAVTQIHLLPGQCQLVTLLDDNSLHLWSLKVKGGASELQEDESFTLR
  GPPGAAPSATQITVVLPHSSCELLYLGTESGNVFVVQLPAFRALEDRTISSDAVLQRLPE
  EARHRRVFEMVEALQEHPRDPNQILIGYSRGLVVIWDLQGSRVLYHFLSSQQLENIWWQR
  DGRLLVSCHSDGSYCQWPVSSEAQQPEPLRSLVPYGPFPCKAITRILWLTTRQGLPFTIF
  QGGMPRASYGDRHCISVIHDGQQTAFDFTSRVIGFTVLTEADPAATFDDPYALVVLAEEE
  LVVIDLQTAGWPPVQLPYLASLHCSAITCSHHVSNIPLKLWERIIAAGSRQNAHFSTMEW
  PIDGGTSLTPAPPQRDLLLTGHEDGTVRFWDASGVCLRLLYKLSTVRVFLTDTDPNENFS
  AQGEDEWPPLRKVGSFDPYSDDPRLGIQKIFLCKYSGYLAVAGTAGQVLVLELNDEAAEQ
  AVEQVEADLLQDQEGYRWKGHERLAARSGPVRFEPGFQPFVLVQCQPPAVVTSLALHSEW
  RLVAFGTSHGFGLFDHQQRRQVFVKCTLHPSDQLALEGPLSRVKSLKKSLRQSFRRMRRS
  RVSSRKRHPAGPPGEAQEGSAKAERPGLQNMELAPVQRKIEARSAEDSFTGFVRTLYFAD
  TYLKDSSRHCPSLWAGTNGGTIYAFSLRVPPAERRMDEPVRAEQAKEIQLMHRAPVVGIL
  VLDGHSVPLPEPLEVAHDLSKSPDMQGSHQLLVVSEEQFKVFTLPKVSAKLKLKLTALEG
  SRVRRVSVAHFGSRRAEDYGEHHLAVLTNLGDIQVVSLPLLKPQVRYSCIRREDVSGIAS
  CVFTKYGQGFYLISPSEFERFSLSTKWLVEPRCLVDSAETKNHRPGNGAGPKKAPSRARN
  SGTQSDGEEKQPGLVMERALLSDERVLKEIQSTLEGDRGSGNWRSHRAAVGCSLSNGGAE
• Function: Part of a complex with GPSM2/LGN, PRKCI/aPKC and PARD6B/Par-6, which may ensure the correct organization and orientation of bipolar spindles for normal cell division. This complex plays roles in the initial phase of the establishment of epithelial cell polarity.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Human papillomavirus infection (hsa05165)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[3]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[3]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	LLGL scribble cell polarity complex component 2 (LLGL2) decreases the response to substance of Arsenic trioxide.	[21]

5 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 LLGL scribble cell polarity complex component 2 (LLGL2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of LLGL scribble cell polarity complex component 2 (LLGL2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of LLGL scribble cell polarity complex component 2 (LLGL2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of LLGL scribble cell polarity complex component 2 (LLGL2).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of LLGL scribble cell polarity complex component 2 (LLGL2).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[12]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[19]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of LLGL scribble cell polarity complex component 2 (LLGL2).	[20]

References

• [1] LLGL2 rescues nutrient stress by promoting leucine uptake in ER(+) breast cancer.Nature. 2019 May;569(7755):275-279. doi: 10.1038/s41586-019-1126-2. Epub 2019 Apr 17.
• [2] A ROR1-HER3-lncRNA signalling axis modulates the Hippo-YAP pathway to regulate bone metastasis.Nat Cell Biol. 2017 Feb;19(2):106-119. doi: 10.1038/ncb3464. Epub 2017 Jan 23.
• [3] Hugl-1 induces apoptosis in esophageal carcinoma cells both in vitro and in vivo.World J Gastroenterol. 2013 Jul 14;19(26):4127-36. doi: 10.3748/wjg.v19.i26.4127.
• [4] Deregulation of the cell polarity protein Lethal giant larvae 2 (Lgl2) correlates with gastric cancer progression.Gastric Cancer. 2014 Oct;17(4):610-20. doi: 10.1007/s10120-013-0324-0. Epub 2013 Dec 13.
• [5] Association of genetic variants with hypertension in a longitudinal population-based genetic epidemiological study.Int J Mol Med. 2015 May;35(5):1189-98. doi: 10.3892/ijmm.2015.2151. Epub 2015 Mar 20.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [11] 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.
• [12] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [13] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [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.