Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWZH4O9)

• DOT Name: Protein LDOC1 (LDOC1)
• Synonyms: Leucine zipper protein down-regulated in cancer cells
• Gene Name: LDOC1
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Neoplasm
  Acute myelogenous leukaemia
  Ewing sarcoma/peripheral primitive neuroectodermal tumor
  Head-neck squamous cell carcinoma
  High blood pressure
  Klinefelter syndrome
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Non-small-cell lung cancer
  Pancreatic tumour
  Parkinson disease
  Precancerous condition
  Squamous cell carcinoma
  Small lymphocytic lymphoma
  Advanced cancer
  Bone osteosarcoma
  Epithelial ovarian cancer
  Metastatic malignant neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Thyroid gland papillary carcinoma
• UniProt ID: LDOC1_HUMAN
• Pfam ID: PF16297
• Sequence:
  MVDELVLLLHALLMRHRALSIENSQLMEQLRLLVCERASLLRQVRPPSCPVPFPETFNGE
  SSRLPEFIVQTASYMLVNENRFCNDAMKVAFLISLLTGEAEEWVVPYIEMDSPILGDYRA
  FLDEMKQCFGWDDDEDDDDEEEEDDY
• Function: May have an important role in the development and/or progression of some cancers.
• Tissue Specificity: Ubiquitously expressed with high levels in brain ant thyroid and low expression in placenta, liver and leukocytes. Expressed as well in six of the seven human breast cancer cell lines examined.

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Biomarker	[1]
Cervical carcinoma	DIST4S00	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[3]
Ewing sarcoma/peripheral primitive neuroectodermal tumor	DISD4VQC	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[5]
High blood pressure	DISY2OHH	Strong	Biomarker	[6]
Klinefelter syndrome	DISOUI7W	Strong	Biomarker	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[10]
Parkinson disease	DISQVHKL	Strong	Altered Expression	[5]
Precancerous condition	DISV06FL	Strong	Altered Expression	[9]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[11]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[8]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[13]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[2]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[2]
Ovarian cancer	DISZJHAP	Limited	Biomarker	[13]
Ovarian neoplasm	DISEAFTY	Limited	Biomarker	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Altered Expression	[14]

13 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 Protein LDOC1 (LDOC1).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein LDOC1 (LDOC1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein LDOC1 (LDOC1).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein LDOC1 (LDOC1).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein LDOC1 (LDOC1).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein LDOC1 (LDOC1).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein LDOC1 (LDOC1).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Protein LDOC1 (LDOC1).	[22]
Marinol	DM70IK5	Approved	Marinol increases the expression of Protein LDOC1 (LDOC1).	[23]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Protein LDOC1 (LDOC1).	[24]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Protein LDOC1 (LDOC1).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein LDOC1 (LDOC1).	[27]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein LDOC1 (LDOC1).	[28]

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 affects the methylation of Protein LDOC1 (LDOC1).	[26]

References

• [1] Loss of LDOC1 expression by promoter methylation in cervical cancer cells.Cancer Invest. 2013 Nov;31(9):571-7. doi: 10.3109/07357907.2013.845671. Epub 2013 Oct 14.
• [2] LDOC1 regulates Wnt5a expression and osteosarcoma cell metastasis and is correlated with the survival of osteosarcoma patients.Tumour Biol. 2017 Feb;39(2):1010428317691188. doi: 10.1177/1010428317691188.
• [3] Acute myeloid leukemia cells secrete microRNA-4532-containing exosomes to mediate normal hematopoiesis in hematopoietic stem cells by activating the LDOC1-dependent STAT3 signaling pathway.Stem Cell Res Ther. 2019 Dec 16;10(1):384. doi: 10.1186/s13287-019-1475-7.
• [4] Potential downstream target genes of aberrant ETS transcription factors are differentially affected in Ewing's sarcoma and prostate carcinoma.PLoS One. 2012;7(11):e49819. doi: 10.1371/journal.pone.0049819. Epub 2012 Nov 19.
• [5] LDOC1 gene expression in two patients with head and neck squamous cell carcinomas and Parkinson's disease.Tumori. 2012 May-Jun;98(3):86e-88e. doi: 10.1700/1125.12418.
• [6] A neural network model for constructing endophenotypes of common complex diseases: an application to male young-onset hypertension microarray data.Bioinformatics. 2009 Apr 15;25(8):981-8. doi: 10.1093/bioinformatics/btp106. Epub 2009 Feb 23.
• [7] LDOC1 Gene Expression in Men With Klinefelter Syndrome.J Clin Lab Anal. 2016 Sep;30(5):408-10. doi: 10.1002/jcla.21870. Epub 2016 Apr 13.
• [8] Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer.Cancers (Basel). 2019 Jan 9;11(1):63. doi: 10.3390/cancers11010063.
• [9] LDOC1 silenced by cigarette exposure and involved in oral neoplastic transformation.Oncotarget. 2015 Sep 22;6(28):25188-201. doi: 10.18632/oncotarget.4512.
• [10] Leucine-zipper protein, LDOC1, inhibits NF-kappaB activation and sensitizes pancreatic cancer cells to apoptosis.Int J Cancer. 2003 Jul 1;105(4):454-8. doi: 10.1002/ijc.11122.
• [11] Epigenetic regulation of the X-linked tumour suppressors BEX1 and LDOC1 in oral squamous cell carcinoma.J Pathol. 2013 Jul;230(3):298-309. doi: 10.1002/path.4173. Epub 2013 Mar 21.
• [12] LDOC1 mRNA is differentially expressed in chronic lymphocytic leukemia and predicts overall survival in untreated patients.Blood. 2011 Apr 14;117(15):4076-84. doi: 10.1182/blood-2010-09-304881. Epub 2011 Feb 10.
• [13] Epigenetic silencing of the LDOC1 tumor suppressor gene in ovarian cancer cells.Arch Gynecol Obstet. 2014 Jul;290(1):149-54. doi: 10.1007/s00404-014-3177-9. Epub 2014 Feb 21.
• [14] LDOC1 inhibits proliferation and promotes apoptosis by repressing NF-B activation in papillary thyroid carcinoma.J Exp Clin Cancer Res. 2015 Dec 4;34:146. doi: 10.1186/s13046-015-0265-z.
• [15] 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.
• [16] 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.
• [17] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [18] 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.
• [19] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [20] 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.
• [21] 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.
• [22] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [23] 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.
• [24] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [25] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [26] 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.
• [27] 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.
• [28] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.