Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTSTC5B5)

• DOT Name: StAR-related lipid transfer protein 3 (STARD3)
• Synonyms: Metastatic lymph node gene 64 protein; MLN 64; Protein CAB1; START domain-containing protein 3; StARD3
• Gene Name: STARD3
• Related Disease:
  Prostate cancer
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Gastric cancer
  Neoplasm
  Osteoporosis
  Prostate carcinoma
  Prostate neoplasm
  Signet ring cell carcinoma
  Stomach cancer
• UniProt ID: STAR3_HUMAN
• PDB ID: 1EM2; 5I9J; 6TQR; 6TQU
• Pfam ID: PF10457 ; PF01852
• Sequence:
  MSKLPRELTRDLERSLPAVASLGSSLSHSQSLSSHLLPPPEKRRAISDVRRTFCLFVTFD
  LLFISLLWIIELNTNTGIRKNLEQEIIQYNFKTSFFDIFVLAFFRFSGLLLGYAVLRLRH
  WWVIAVTTLVSSAFLIVKVILSELLSKGAFGYLLPIVSFVLAWLETWFLDFKVLPQEAEE
  ERWYLAAQVAVARGPLLFSGALSEGQFYSPPESFAGSDNESDEEVAGKKSFSAQEREYIR
  QGKEATAVVDQILAQEENWKFEKNNEYGDTVYTIEVPFHGKTFILKTFLPCPAELVYQEV
  ILQPERMVLWNKTVTACQILQRVEDNTLISYDVSAGAAGGVVSPRDFVNVRRIERRRDRY
  LSSGIATSHSAKPPTHKYVRGENGPGGFIVLKSASNPRVCTFVWILNTDLKGRLPRYLIH
  QSLAATMFEFAFHLRQRISELGARA
• Function: Sterol-binding protein that mediates cholesterol transport from the endoplasmic reticulum to endosomes. The sterol transport mechanism is triggered by phosphorylation of FFAT motif that leads to membrane tethering between the endoplasmic reticulum and late endosomes via interaction with VAPA and VAPB. Acts as a lipid transfer protein that redirects sterol to the endosome at the expense of the cell membrane and favors membrane formation inside endosomes. May also mediate cholesterol transport between other membranes, such as mitochondria membrane or cell membrane. However, such results need additional experimental evidences; probably mainly mediates cholesterol transport from the endoplasmic reticulum to endosomes. Does not activate transcriptional cholesterol sensing. Able to bind other lipids, such as lutein, a xanthophyll carotenoids that form the macular pigment of the retina.
• Tissue Specificity: Expressed in retina.
• KEGG Pathway: Cholesterol metabolism (hsa04979)
• Reactome Pathway: Pregnenolone biosynthesis (R-HSA-196108)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Osteoporosis	DISF2JE0	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[9]
Signet ring cell carcinoma	DISVCUCR	Strong	Genetic Variation	[10]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]

2 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 StAR-related lipid transfer protein 3 (STARD3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of StAR-related lipid transfer protein 3 (STARD3).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of StAR-related lipid transfer protein 3 (STARD3).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of StAR-related lipid transfer protein 3 (STARD3).	[14]

References

• [1] First-of-its-kind STARD(3) Inhibitor: In Silico Identification and Biological Evaluation as Anticancer Agent.ACS Med Chem Lett. 2019 Feb 20;10(4):475-480. doi: 10.1021/acsmedchemlett.8b00509. eCollection 2019 Apr 11.
• [2] Elevated levels of StAR-related lipid transfer protein 3 alter cholesterol balance and adhesiveness of breast cancer cells: potential mechanisms contributing to progression of HER2-positive breast cancers.Am J Pathol. 2015 Apr;185(4):987-1000. doi: 10.1016/j.ajpath.2014.12.018. Epub 2015 Feb 12.
• [3] Expression of MLN64 influences cellular matrix adhesion of breast cancer cells, the role for focal adhesion kinase.Int J Mol Med. 2010 Apr;25(4):573-80.
• [4] High efficiency reconstitution of a human-mouse chimeric Fab of CAb-1 antibody specific to human colon cancer.Scand J Immunol. 2008 Jul;68(1):12-21. doi: 10.1111/j.1365-3083.2008.02087.x. Epub 2008 May 13.
• [5] PPP1R1B-STARD3 chimeric fusion transcript in human gastric cancer promotes tumorigenesis through activation of PI3K/AKT signaling.Oncogene. 2014 Nov 13;33(46):5341-7. doi: 10.1038/onc.2013.472. Epub 2013 Nov 25.
• [6] Ioncopy: anovel method for calling copy number alterations in amplicon sequencing data including significance assessment.Oncotarget. 2016 Mar 15;7(11):13236-47. doi: 10.18632/oncotarget.7451.
• [7] MLN64 deletion suppresses RANKL-induced osteoclastic differentiation and attenuates diabetic osteoporosis in streptozotocin (STZ)-induced mice.Biochem Biophys Res Commun. 2018 Nov 10;505(4):1228-1235. doi: 10.1016/j.bbrc.2018.10.007. Epub 2018 Oct 13.
• [8] Increased metastatic lymph node 64 and CYP17 expression are associated with high stage prostate cancer.J Endocrinol. 2007 Jul;194(1):55-61. doi: 10.1677/JOE-07-0131.
• [9] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [10] Association analysis of ERBB2 amplicon genetic polymorphisms and STARD3 expression with risk of gastric cancer in the Chinese population.Gene. 2014 Feb 10;535(2):225-32. doi: 10.1016/j.gene.2013.11.030. Epub 2013 Nov 28.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.