Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVDL515)

• DOT Name: Guanine nucleotide-binding protein subunit alpha-13 (GNA13)
• Synonyms: G alpha-13; G-protein subunit alpha-13
• Gene Name: GNA13
• Related Disease:
  Metastatic malignant neoplasm
  Adult lymphoma
  Advanced cancer
  B-cell lymphoma
  Bone disease
  Breast cancer
  Breast carcinoma
  Burkitt lymphoma
  Central nervous system lymphoma
  Clear cell renal carcinoma
  Coeliac disease
  Colorectal carcinoma
  Hepatocellular carcinoma
  Hyperinsulinemia
  Isovaleric acidemia
  Lymphoma
  Metabolic disorder
  Obesity
  Pediatric lymphoma
  Prostate neoplasm
  Renal cell carcinoma
  Schizophrenia
  Melanoma
  Osteoarthritis
  Prostate cancer
  Prostate carcinoma
  Follicular lymphoma
  Neoplasm
  Convulsion
  Head-neck squamous cell carcinoma
• UniProt ID: GNA13_HUMAN
• PDB ID: 7SF7; 7SF8; 7T6B; 7YDH; 8H8J
• Pfam ID: PF00503
• Sequence:
  MADFLPSRSVLSVCFPGCLLTSGEAEQQRKSKEIDKCLSREKTYVKRLVKILLLGAGESG
  KSTFLKQMRIIHGQDFDQRAREEFRPTIYSNVIKGMRVLVDAREKLHIPWGDNSNQQHGD
  KMMSFDTRAPMAAQGMVETRVFLQYLPAIRALWADSGIQNAYDRRREFQLGESVKYFLDN
  LDKLGEPDYIPSQQDILLARRPTKGIHEYDFEIKNVPFKMVDVGGQRSERKRWFECFDSV
  TSILFLVSSSEFDQVLMEDRLTNRLTESLNIFETIVNNRVFSNVSIILFLNKTDLLEEKV
  QIVSIKDYFLEFEGDPHCLRDVQKFLVECFRNKRRDQQQKPLYHHFTTAINTENIRLVFR
  DVKDTILHDNLKQLMLQ
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF1/p115RhoGEF, ARHGEF11/PDZ-RhoGEF and ARHGEF12/LARG). GNA13-dependent Rho signaling subsequently regulates transcription factor AP-1 (activating protein-1). Promotes tumor cell invasion and metastasis by activating RhoA/ROCK signaling pathway. Inhibits CDH1-mediated cell adhesion in process independent from Rho activation.
• Tissue Specificity: Expressed in testis, including in Leydig cells and in the seminiferous epithelium, in differentiating cells from the spermatogonia to mature spermatozoa stages and round spermatids (at protein level). Expressed in 99.2% of spermatozoa from healthy individuals, but only in 28.6% of macrocephalic spermatozoa from infertile patients (at protein level).
• KEGG Pathway:
  cGMP-PKG sig.ling pathway (hsa04022)
  Sphingolipid sig.ling pathway (hsa04071)
  Phospholipase D sig.ling pathway (hsa04072)
  Vascular smooth muscle contraction (hsa04270)
  Apelin sig.ling pathway (hsa04371)
  Platelet activation (hsa04611)
  Long-term depression (hsa04730)
  Regulation of actin cytoskeleton (hsa04810)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Pathogenic Escherichia coli infection (hsa05130)
  Human cytomegalovirus infection (hsa05163)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metastatic malignant neoplasm	DIS86UK6	Definitive	Altered Expression	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[4]
Bone disease	DISE1F82	Strong	Altered Expression	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[7]
Central nervous system lymphoma	DISBYQTA	Strong	Genetic Variation	[8]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[9]
Coeliac disease	DISIY60C	Strong	Biomarker	[10]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[13]
Isovaleric acidemia	DIS3ETX9	Strong	Biomarker	[14]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[13]
Obesity	DIS47Y1K	Strong	Biomarker	[13]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[15]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[9]
Schizophrenia	DISSRV2N	Strong	Biomarker	[16]
Melanoma	DIS1RRCY	moderate	Altered Expression	[17]
Osteoarthritis	DIS05URM	moderate	Biomarker	[18]
Prostate cancer	DISF190Y	moderate	Altered Expression	[19]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[19]
Follicular lymphoma	DISVEUR6	Disputed	Altered Expression	[20]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[1]
Convulsion	DIS1CYA2	Limited	Biomarker	[1]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Biomarker	[1]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[23]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[26]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[27]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[28]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[29]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[30]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[29]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[31]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[35]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[36]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
5'-Guanosine-Diphosphate-Monothiophosphate	DMIARG7	Investigative	5'-Guanosine-Diphosphate-Monothiophosphate affects the binding of Guanine nucleotide-binding protein subunit alpha-13 (GNA13).	[37]

References

• [1] GNA13 expression promotes drug resistance and tumor-initiating phenotypes in squamous cell cancers.Oncogene. 2018 Mar;37(10):1340-1353. doi: 10.1038/s41388-017-0038-6. Epub 2017 Dec 19.
• [2] Loss of signalling via G13 in germinal centre B-cell-derived lymphoma.Nature. 2014 Dec 11;516(7530):254-8. doi: 10.1038/nature13765. Epub 2014 Sep 28.
• [3] GNA13 promotes tumor growth and angiogenesis by upregulating CXC chemokines via the NF-B signaling pathway in colorectal cancer cells.Cancer Med. 2018 Nov;7(11):5611-5620. doi: 10.1002/cam4.1783. Epub 2018 Sep 28.
• [4] Pharmacological DNA demethylation restores SMAD1 expression and tumor suppressive signaling in diffuse large B-cell lymphoma.Blood Adv. 2019 Oct 22;3(20):3020-3032. doi: 10.1182/bloodadvances.2019000210.
• [5] G13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3-NFATc1 signalling pathway.Nat Commun. 2017 Jan 19;8:13700. doi: 10.1038/ncomms13700.
• [6] MicroRNA-31 controls G protein alpha-13 (GNA13) expression and cell invasion in breast cancer cells.Mol Cancer. 2015 Mar 26;14:67. doi: 10.1186/s12943-015-0337-x.
• [7] Inactivating mutations in GNA13 and RHOA in Burkitt's lymphoma and diffuse large B-cell lymphoma: a tumor suppressor function for the G13/RhoA axis in B cells.Oncogene. 2016 Jul 21;35(29):3771-80. doi: 10.1038/onc.2015.442. Epub 2015 Nov 30.
• [8] Analysis of Genomic Alteration in Primary Central Nervous System Lymphoma and the Expression of Some Related Genes.Neoplasia. 2018 Oct;20(10):1059-1069. doi: 10.1016/j.neo.2018.08.012. Epub 2018 Sep 15.
• [9] MiR-30b-5p functions as a tumor suppressor in cell proliferation, metastasis and epithelial-to-mesenchymal transition by targeting G-protein subunit -13 in renal cell carcinoma.Gene. 2017 Aug 30;626:275-281. doi: 10.1016/j.gene.2017.05.040. Epub 2017 May 20.
• [10] Angiogenesis-related gene expression analysis in celiac disease.Autoimmunity. 2012 May;45(3):264-70. doi: 10.3109/08916934.2011.637531. Epub 2012 Jan 9.
• [11] miRNA-30d serves a critical function in colorectal cancer initiation, progression and invasion via directly targeting the GNA13 gene.Exp Ther Med. 2019 Jan;17(1):260-272. doi: 10.3892/etm.2018.6902. Epub 2018 Oct 30.
• [12] High expression of GNA13 is associated with poor prognosis in hepatocellular carcinoma.Sci Rep. 2016 Nov 24;6:35948. doi: 10.1038/srep35948.
• [13] G13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism.J Clin Invest. 2017 Oct 2;127(10):3845-3860. doi: 10.1172/JCI92067. Epub 2017 Sep 18.
• [14] MiR-29c mediates epithelial-to-mesenchymal transition in human colorectal carcinoma metastasis via PTP4A and GNA13 regulation of -catenin signaling.Ann Oncol. 2014 Nov;25(11):2196-2204. doi: 10.1093/annonc/mdu439. Epub 2014 Sep 5.
• [15] A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion.J Biol Chem. 2006 Sep 8;281(36):26483-90. doi: 10.1074/jbc.M604376200. Epub 2006 Jun 20.
• [16] The role of genes affected by human evolution marker GNA13 in schizophrenia.Prog Neuropsychopharmacol Biol Psychiatry. 2020 Mar 2;98:109764. doi: 10.1016/j.pnpbp.2019.109764. Epub 2019 Oct 30.
• [17] G13 mediates human cytomegalovirus-encoded chemokine receptor US28-induced cell death in melanoma.Int J Cancer. 2015 Sep 15;137(6):1503-8. doi: 10.1002/ijc.29506. Epub 2015 Mar 16.
• [18] Exploring the Key Genes and Pathways of Osteoarthritis in Knee Cartilage in a Rat Model Using Gene Expression Profiling.Yonsei Med J. 2018 Aug;59(6):760-768. doi: 10.3349/ymj.2018.59.6.760.
• [19] G-13 induces CXC motif chemokine ligand 5 expression in prostate cancer cells by transactivating NF-B.J Biol Chem. 2019 Nov 29;294(48):18192-18206. doi: 10.1074/jbc.RA119.010018. Epub 2019 Oct 21.
• [20] Analysis of GNA13 Protein in Follicular Lymphoma and its Association With Poor Prognosis.Am J Surg Pathol. 2018 Nov;42(11):1466-1471. doi: 10.1097/PAS.0000000000000969.
• [21] 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.
• [22] 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.
• [23] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [24] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [25] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [26] 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.
• [27] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [28] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [29] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [30] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] 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.
• [33] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [34] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [35] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [36] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.
• [37] The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007 Dec;152(7):1092-101.