Details of Drug Off-Target (DOT)

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

• DOT Name: Lipid scramblase CLPTM1L (CLPTM1L)
• Synonyms: Cisplatin resistance-related protein 9; CRR9p; Cleft lip and palate transmembrane protein 1-like protein; CLPTM1-like protein
• Gene Name: CLPTM1L
• Related Disease:
  Colorectal carcinoma
  Cutaneous melanoma
  Ovarian neoplasm
  Adenocarcinoma
  Advanced cancer
  Bladder cancer
  Breast cancer
  Carcinoma of esophagus
  Cleft lip/palate
  Esophageal cancer
  Glioma
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Lung neoplasm
  Lung squamous cell carcinoma
  Lymphoid leukemia
  Nasopharyngeal carcinoma
  Neoplasm
  Neoplasm of esophagus
  Oral cancer
  Pancreatic tumour
  Uveal Melanoma
  Benign prostatic hyperplasia
  Breast carcinoma
  Melanoma
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Squamous cell carcinoma
  Small lymphocytic lymphoma
  Urinary bladder cancer
  Basal cell carcinoma
  Basal cell neoplasm
  Colon cancer
  Colon carcinoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Lung adenocarcinoma
  Prostate cancer
  Prostate neoplasm
  Thyroid gland papillary carcinoma
  Urinary bladder neoplasm
  Uterine cervix neoplasm
• UniProt ID: CLP1L_HUMAN
• Pfam ID: PF05602
• Sequence:
  MWSGRSSFTSLVVGVFVVYVVHTCWVMYGIVYTRPCSGDANCIQPYLARRPKLQLSVYTT
  TRSHLGAENNIDLVLNVEDFDVESKFERTVNVSVPKKTRNNGTLYAYIFLHHAGVLPWHD
  GKQVHLVSPLTTYMVPKPEEINLLTGESDTQQIEAEKKPTSALDEPVSHWRPRLALNVMA
  DNFVFDGSSLPADVHRYMKMIQLGKTVHYLPILFIDQLSNRVKDLMVINRSTTELPLTVS
  YDKVSLGRLRFWIHMQDAVYSLQQFGFSEKDADEVKGIFVDTNLYFLALTFFVAAFHLLF
  DFLAFKNDISFWKKKKSMIGMSTKAVLWRCFSTVVIFLFLLDEQTSLLVLVPAGVGAAIE
  LWKVKKALKMTIFWRGLMPEFQFGTYSESERKTEEYDTQAMKYLSYLLYPLCVGGAVYSL
  LNIKYKSWYSWLINSFVNGVYAFGFLFMLPQLFVNYKLKSVAHLPWKAFTYKAFNTFIDD
  VFAFIITMPTSHRLACFRDDVVFLVYLYQRWLYPVDKRRVNEFGESYEEKATRAPHTD
• Function: Scramblase that mediates the translocation of glucosaminylphosphatidylinositol (alpha-D-GlcN-(1-6)-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol, GlcN-PI) across the endoplasmic reticulum (ER) membrane, from the cytosolic leaflet to the luminal leaflet of the ER membrane, where it participates in the biosynthesis of glycosylphosphatidylinositol (GPI). GPI is a lipid glycoconjugate involved in post-translational modification of proteins. Can also translocate 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) (phosphatidylinositol or PI), as well as several other phospholipids (1,2-diacyl-sn-glycero-3-phosphocholine, 1,2-diacyl-sn-glycero-3-phosphoethanolamine), and N-acetylglucosaminylphosphatidylinositol (GlcNAc-PI) in vitro.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[1]
Cutaneous melanoma	DIS3MMH9	Definitive	Genetic Variation	[2]
Ovarian neoplasm	DISEAFTY	Definitive	Altered Expression	[3]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[6]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[7]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[8]
Cleft lip/palate	DIS14IG3	Strong	Biomarker	[9]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[8]
Glioma	DIS5RPEH	Strong	Genetic Variation	[10]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[12]
Lung neoplasm	DISVARNB	Strong	Biomarker	[13]
Lung squamous cell carcinoma	DISXPIBD	Strong	Genetic Variation	[14]
Lymphoid leukemia	DIS65TYQ	Strong	Biomarker	[15]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[16]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[8]
Oral cancer	DISLD42D	Strong	Genetic Variation	[17]
Pancreatic tumour	DIS3U0LK	Strong	Posttranslational Modification	[18]
Uveal Melanoma	DISA7ZGL	Strong	Genetic Variation	[19]
Benign prostatic hyperplasia	DISI3CW2	moderate	Genetic Variation	[20]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[7]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[21]
Pancreatic cancer	DISJC981	moderate	Biomarker	[9]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Biomarker	[22]
Squamous cell carcinoma	DISQVIFL	moderate	Genetic Variation	[23]
Small lymphocytic lymphoma	DIS30POX	Disputed	Genetic Variation	[15]
Urinary bladder cancer	DISDV4T7	Disputed	Genetic Variation	[6]
Basal cell carcinoma	DIS7PYN3	Limited	Genetic Variation	[24]
Basal cell neoplasm	DIS37IXW	Limited	Genetic Variation	[24]
Colon cancer	DISVC52G	Limited	Genetic Variation	[25]
Colon carcinoma	DISJYKUO	Limited	Genetic Variation	[25]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[26]
Esophageal squamous cell carcinoma	DIS5N2GV	Limited	Genetic Variation	[8]
Lung adenocarcinoma	DISD51WR	Limited	Genetic Variation	[27]
Prostate cancer	DISF190Y	Limited	Biomarker	[28]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[28]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Genetic Variation	[29]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[28]
Uterine cervix neoplasm	DIS0BYVV	Limited	Biomarker	[28]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Lipid scramblase CLPTM1L (CLPTM1L) increases the response to substance of Cisplatin.	[39]
Camptothecin	DM6CHNJ	Phase 3	Lipid scramblase CLPTM1L (CLPTM1L) increases the response to substance of Camptothecin.	[39]

3 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 Lipid scramblase CLPTM1L (CLPTM1L).	[30]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Lipid scramblase CLPTM1L (CLPTM1L).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Lipid scramblase CLPTM1L (CLPTM1L).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Lipid scramblase CLPTM1L (CLPTM1L).	[31]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Lipid scramblase CLPTM1L (CLPTM1L).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Lipid scramblase CLPTM1L (CLPTM1L).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Lipid scramblase CLPTM1L (CLPTM1L).	[36]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Lipid scramblase CLPTM1L (CLPTM1L).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Lipid scramblase CLPTM1L (CLPTM1L).	[38]

References

• [1] The TERT variant rs2736100 is associated with colorectal cancer risk.Br J Cancer. 2012 Sep 4;107(6):1001-8. doi: 10.1038/bjc.2012.329. Epub 2012 Aug 9.
• [2] Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways.Nat Commun. 2018 Nov 14;9(1):4774. doi: 10.1038/s41467-018-06649-5.
• [3] A novel gene, CRR9, which was up-regulated in CDDP-resistant ovarian tumor cell line, was associated with apoptosis.Biochem Biophys Res Commun. 2001 Feb 2;280(4):1148-54. doi: 10.1006/bbrc.2001.4250.
• [4] Decreased risk of developing lung cancer in subjects carrying the CLPTM1L rs401681 (G>A) polymorphism: evidence from a meta-analysis.Genet Mol Res. 2014 Feb 28;13(1):1373-82. doi: 10.4238/2014.February.28.10.
• [5] Pathobiological role of cleft palate transmembrane protein 1 family proteins in oral squamous cell carcinoma.J Cancer Res Clin Oncol. 2019 Apr;145(4):851-859. doi: 10.1007/s00432-019-02843-0. Epub 2019 Jan 11.
• [6] Genome-wide association study identifies multiple loci associated with bladder cancer risk.Hum Mol Genet. 2014 Mar 1;23(5):1387-98. doi: 10.1093/hmg/ddt519. Epub 2013 Oct 24.
• [7] Lack of association between common single nucleotide polymorphisms in the TERT-CLPTM1L locus and breast cancer in women of African ancestry.Breast Cancer Res Treat. 2012 Feb;132(1):341-5. doi: 10.1007/s10549-011-1890-7. Epub 2011 Nov 29.
• [8] The identification of two regulatory ESCC susceptibility genetic variants in the TERT-CLPTM1L loci.Oncotarget. 2016 Feb 2;7(5):5495-506. doi: 10.18632/oncotarget.6747.
• [9] CLPTM1L/CRR9 ectodomain interaction with GRP78 at the cell surface signals for survival and chemoresistance upon ER stress in pancreatic adenocarcinoma cells.Int J Cancer. 2019 Mar 15;144(6):1367-1378. doi: 10.1002/ijc.32012. Epub 2019 Jan 3.
• [10] Fine-mapping of a region of chromosome 5p15.33 (TERT-CLPTM1L) suggests a novel locus in TERT and a CLPTM1L haplotype are associated with glioma susceptibility in a Chinese population.Int J Cancer. 2012 Oct 1;131(7):1569-76. doi: 10.1002/ijc.27417. Epub 2012 Mar 2.
• [11] Genetic variations in TERT-CLPTM1L genes and risk of squamous cell carcinoma of the head and neck.Carcinogenesis. 2010 Nov;31(11):1977-81. doi: 10.1093/carcin/bgq179. Epub 2010 Aug 28.
• [12] Polymorphisms of TERT and CLPTM1L and the risk of hepatocellular carcinoma in Chinese males.Asian Pac J Cancer Prev. 2014;15(19):8197-201. doi: 10.7314/apjcp.2014.15.19.8197.
• [13] CRR9/CLPTM1L regulates cell survival signaling and is required for Ras transformation and lung tumorigenesis.Cancer Res. 2014 Feb 15;74(4):1116-27. doi: 10.1158/0008-5472.CAN-13-1617. Epub 2013 Dec 23.
• [14] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [15] A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia.Nat Genet. 2014 Jan;46(1):56-60. doi: 10.1038/ng.2843. Epub 2013 Dec 1.
• [16] Leukocyte telomere length associates with nasopharyngeal carcinoma risk and survival in Hong Kong Chinese.Int J Cancer. 2018 Nov 1;143(9):2289-2298. doi: 10.1002/ijc.31617. Epub 2018 Aug 7.
• [17] Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer.Nat Genet. 2016 Dec;48(12):1544-1550. doi: 10.1038/ng.3685. Epub 2016 Oct 17.
• [18] Novel Anti-CRR9/CLPTM1L Antibodies with Antitumorigenic Activity Inhibit Cell Surface Accumulation, PI3K Interaction, and Survival Signaling.Mol Cancer Ther. 2016 May;15(5):985-97. doi: 10.1158/1535-7163.MCT-15-0717. Epub 2016 Mar 3.
• [19] Genome-wide study on uveal melanoma patients finds association to DNA repair gene TDP1.Melanoma Res. 2020 Apr;30(2):166-172. doi: 10.1097/CMR.0000000000000641.
• [20] Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA.Nat Commun. 2018 Nov 8;9(1):4568. doi: 10.1038/s41467-018-06920-9.
• [21] Assessing a single SNP located at TERT/CLPTM1L multi-cancer risk region as a genetic modifier for risk of pancreatic cancer and melanoma in Dutch CDKN2A mutation carriers.Fam Cancer. 2019 Oct;18(4):439-444. doi: 10.1007/s10689-019-00137-5.
• [22] CLPTM1L promotes growth and enhances aneuploidy in pancreatic cancer cells.Cancer Res. 2014 May 15;74(10):2785-95. doi: 10.1158/0008-5472.CAN-13-3176. Epub 2014 Mar 19.
• [23] Genetic variants in telomere-maintaining genes and skin cancer risk.Hum Genet. 2011 Mar;129(3):247-53. doi: 10.1007/s00439-010-0921-5. Epub 2010 Nov 30.
• [24] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [25] TERT's role in colorectal carcinogenesis.Mol Carcinog. 2013 Jul;52(7):507-13. doi: 10.1002/mc.21885. Epub 2012 Feb 21.
• [26] Functional polymorphisms in the TERT promoter are associated with risk of serous epithelial ovarian and breast cancers.PLoS One. 2011;6(9):e24987. doi: 10.1371/journal.pone.0024987. Epub 2011 Sep 15.
• [27] Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region.J Thorac Oncol. 2019 Aug;14(8):1360-1369. doi: 10.1016/j.jtho.2019.04.008. Epub 2019 Apr 19.
• [28] Sequence variants at the TERT-CLPTM1L locus associate with many cancer types.Nat Genet. 2009 Feb;41(2):221-7. doi: 10.1038/ng.296. Epub 2009 Jan 18.
• [29] Functional evaluation of TERT-CLPTM1L genetic variants associated with susceptibility of papillary thyroid carcinoma.Sci Rep. 2016 May 17;6:26037. doi: 10.1038/srep26037.
• [30] 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.
• [31] 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.
• [32] 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.
• [33] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [34] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [35] 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.
• [36] 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.
• [37] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [38] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [39] Functional characterization of CLPTM1L as a lung cancer risk candidate gene in the 5p15.33 locus. PLoS One. 2012;7(6):e36116. doi: 10.1371/journal.pone.0036116. Epub 2012 Jun 4.