Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2CL9ST)

• DOT Name: Calcium-binding protein 39 (CAB39)
• Synonyms: MO25alpha; Protein Mo25
• Gene Name: CAB39
• Related Disease:
  Hyperthyroidism
  Colorectal carcinoma
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Hypertrophic cardiomyopathy
  Peutz-Jeghers syndrome
  Stomach cancer
  Pancreatic cancer
• UniProt ID: CAB39_HUMAN
• PDB ID: 1UPK; 1UPL; 2WTK; 3GNI; 4FZA; 4FZD; 4FZF; 4NZW; 4O27
• Pfam ID: PF08569
• Sequence:
  MPFPFGKSHKSPADIVKNLKESMAVLEKQDISDKKAEKATEEVSKNLVAMKEILYGTNEK
  EPQTEAVAQLAQELYNSGLLSTLVADLQLIDFEGKKDVAQIFNNILRRQIGTRTPTVEYI
  CTQQNILFMLLKGYESPEIALNCGIMLRECIRHEPLAKIILWSEQFYDFFRYVEMSTFDI
  ASDAFATFKDLLTRHKLLSAEFLEQHYDRFFSEYEKLLHSENYVTKRQSLKLLGELLLDR
  HNFTIMTKYISKPENLKLMMNLLRDKSRNIQFEAFHVFKVFVANPNKTQPILDILLKNQA
  KLIEFLSKFQNDRTEDEQFNDEKTYLVKQIRDLKRPAQQEA
• Function: Component of a complex that binds and activates STK11/LKB1. In the complex, required to stabilize the interaction between CAB39/MO25 (CAB39/MO25alpha or CAB39L/MO25beta) and STK11/LKB1.
• KEGG Pathway:
  mTOR sig.ling pathway (hsa04150)
  AMPK sig.ling pathway (hsa04152)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hyperthyroidism	DISX87ZH	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[6]
Peutz-Jeghers syndrome	DISF27ZJ	Strong	Biomarker	[7]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Pancreatic cancer	DISJC981	moderate	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calcium-binding protein 39 (CAB39).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Calcium-binding protein 39 (CAB39).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Calcium-binding protein 39 (CAB39).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Calcium-binding protein 39 (CAB39).	[12]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Calcium-binding protein 39 (CAB39).	[13]
Daunorubicin	DMQUSBT	Approved	Daunorubicin decreases the expression of Calcium-binding protein 39 (CAB39).	[13]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Calcium-binding protein 39 (CAB39).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Calcium-binding protein 39 (CAB39).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Calcium-binding protein 39 (CAB39).	[16]

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 Calcium-binding protein 39 (CAB39).	[14]

References

• [1] Thyroid hormone effects on LKB1, MO25, phospho-AMPK, phospho-CREB, and PGC-1alpha in rat muscle.J Appl Physiol (1985). 2008 Oct;105(4):1218-27. doi: 10.1152/japplphysiol.00997.2007. Epub 2008 Jul 31.
• [2] microRNA-451a regulates colorectal cancer proliferation in response to radiation.BMC Cancer. 2018 May 3;18(1):517. doi: 10.1186/s12885-018-4370-1.
• [3] MIR-1265 regulates cellular proliferation and apoptosis by targeting calcium binding protein 39 in gastric cancer and, thereby, impairing oncogenic autophagy.Cancer Lett. 2019 May 1;449:226-236. doi: 10.1016/j.canlet.2019.02.026. Epub 2019 Feb 16.
• [4] MiRNA-451 Inhibits Glioma Cell Proliferation and Invasion Through the mTOR/HIF-1/VEGF Signaling Pathway by Targeting CAB39.Hum Gene Ther Clin Dev. 2018 Sep;29(3):156-166. doi: 10.1089/humc.2018.133.
• [5] Calcium-binding protein 39 promotes hepatocellular carcinoma growth and metastasis by activating extracellular signal-regulated kinase signaling pathway.Hepatology. 2017 Nov;66(5):1529-1545. doi: 10.1002/hep.29312. Epub 2017 Sep 29.
• [6] Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25.PLoS One. 2012;7(7):e41574. doi: 10.1371/journal.pone.0041574. Epub 2012 Jul 23.
• [7] Mutation analysis of three genes encoding novel LKB1-interacting proteins, BRG1, STRADalpha, and MO25alpha, in Peutz-Jeghers syndrome.Br J Cancer. 2005 Mar 28;92(6):1126-9. doi: 10.1038/sj.bjc.6602454.
• [8] MiR-451 Promotes Cell Proliferation and Metastasis in Pancreatic Cancer through Targeting CAB39.Biomed Res Int. 2017;2017:2381482. doi: 10.1155/2017/2381482. Epub 2017 Jan 19.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] Characterization of DNA reactive and non-DNA reactive anticancer drugs by gene expression profiling. Mutat Res. 2007 Jun 1;619(1-2):16-29. doi: 10.1016/j.mrfmmm.2006.12.007. Epub 2007 Feb 8.
• [14] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [15] 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.
• [16] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.