Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYX9YCZ)

• DOT Name: Apoptosis inhibitor 5 (API5)
• Synonyms: API-5; Antiapoptosis clone 11 protein; AAC-11; Cell migration-inducing gene 8 protein; Fibroblast growth factor 2-interacting factor; FIF; Protein XAGL
• Gene Name: API5
• Related Disease:
  Diabetic retinopathy
  Metastatic malignant neoplasm
  Non-insulin dependent diabetes
  Adenocarcinoma
  Adult glioblastoma
  Cervical cancer
  Cervical carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Squamous cell carcinoma
  Advanced cancer
  Lupus nephritis
  Systemic lupus erythematosus
  Breast cancer
  Breast carcinoma
• UniProt ID: API5_HUMAN
• PDB ID: 3U0R; 3V6A; 6L4O
• Pfam ID: PF05918
• Sequence:
  MPTVEELYRNYGILADATEQVGQHKDAYQVILDGVKGGTKEKRLAAQFIPKFFKHFPELA
  DSAINAQLDLCEDEDVSIRRQAIKELPQFATGENLPRVADILTQLLQTDDSAEFNLVNNA
  LLSIFKMDAKGTLGGLFSQILQGEDIVRERAIKFLSTKLKTLPDEVLTKEVEELILTESK
  KVLEDVTGEEFVLFMKILSGLKSLQTVSGRQQLVELVAEQADLEQTFNPSDPDCVDRLLQ
  CTRQAVPLFSKNVHSTRFVTYFCEQVLPNLGTLTTPVEGLDIQLEVLKLLAEMSSFCGDM
  EKLETNLRKLFDKLLEYMPLPPEEAENGENAGNEEPKLQFSYVECLLYSFHQLGRKLPDF
  LTAKLNAEKLKDFKIRLQYFARGLQVYIRQLRLALQGKTGEALKTEENKIKVVALKITNN
  INVLIKDLFHIPPSYKSTVTLSWKPVQKVEIGQKRASEDTTSGSPPKKSSAGPKRDARQI
  YNPPSGKYSSNLGNFNYEQRGAFRGSRGGRGWGTRGNRSRGRLY
• Function: Antiapoptotic factor that may have a role in protein assembly. Negatively regulates ACIN1. By binding to ACIN1, it suppresses ACIN1 cleavage from CASP3 and ACIN1-mediated DNA fragmentation. Also known to efficiently suppress E2F1-induced apoptosis. Its depletion enhances the cytotoxic action of the chemotherapeutic drugs.
• Tissue Specificity: Expressed in all tissues tested, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Highest levels in heart, pancreas and placenta. Highly expressed in several cancers. Preferentially expressed in squamous cell carcinoma versus adenocarcinoma in non-small cell lung cancer.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic retinopathy	DISHGUJM	Definitive	Biomarker	[1]
Metastatic malignant neoplasm	DIS86UK6	Definitive	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[8]
Lupus nephritis	DISCVGPZ	moderate	Altered Expression	[9]
Systemic lupus erythematosus	DISI1SZ7	moderate	Altered Expression	[9]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[10]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Apoptosis inhibitor 5 (API5) decreases the response to substance of Doxorubicin.	[25]

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 Apoptosis inhibitor 5 (API5).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Apoptosis inhibitor 5 (API5).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Apoptosis inhibitor 5 (API5).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Apoptosis inhibitor 5 (API5).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Apoptosis inhibitor 5 (API5).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Apoptosis inhibitor 5 (API5).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Apoptosis inhibitor 5 (API5).	[17]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Apoptosis inhibitor 5 (API5).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Apoptosis inhibitor 5 (API5).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Apoptosis inhibitor 5 (API5).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Apoptosis inhibitor 5 (API5).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Apoptosis inhibitor 5 (API5).	[22]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Apoptosis inhibitor 5 (API5).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Apoptosis inhibitor 5 (API5).	[23]

References

• [1] Common variants in or near ZNRF1, COLEC12, SCYL1BP1 and API5 are associated with diabetic retinopathy in Chinese patients with type 2 diabetes.Diabetologia. 2015 Jun;58(6):1231-8. doi: 10.1007/s00125-015-3569-9. Epub 2015 Mar 28.
• [2] Gene expression levels of CSNK1A1 and AAC-11, but not NME1, in tumor tissues as prognostic factors in NSCLC patients.Med Sci Monit. 2010 Aug;16(8):CR357-64.
• [3] Expression of the antiapoptosis gene, AAC-11, as a prognosis marker in non-small cell lung cancer.Lung Cancer. 2001 Oct;34(1):53-7. doi: 10.1016/s0169-5002(01)00213-6.
• [4] MiR-224 expression increases radiation sensitivity of glioblastoma cells.Biochem Biophys Res Commun. 2014 May 30;448(2):225-30. doi: 10.1016/j.bbrc.2014.04.095. Epub 2014 Apr 29.
• [5] API5 induces cisplatin resistance through FGFR signaling in human cancer cells.Exp Mol Med. 2017 Sep 8;49(9):e374. doi: 10.1038/emm.2017.130.
• [6] Pim-2 activates API-5 to inhibit the apoptosis of hepatocellular carcinoma cells through NF-kappaB pathway.Pathol Oncol Res. 2010 Jun;16(2):229-37. doi: 10.1007/s12253-009-9215-4. Epub 2009 Oct 12.
• [7] API5 confers cancer stem cell-like properties through the FGF2-NANOG axis.Oncogenesis. 2017 Jan 16;6(1):e285. doi: 10.1038/oncsis.2016.87.
• [8] The anticancer peptide RT53 induces immunogenic cell death.PLoS One. 2018 Aug 6;13(8):e0201220. doi: 10.1371/journal.pone.0201220. eCollection 2018.
• [9] Decreased microRNA(miR)-145 and increased miR-224 expression in T cells from patients with systemic lupus erythematosus involved in lupus immunopathogenesis.Clin Exp Immunol. 2013 Jan;171(1):91-9. doi: 10.1111/j.1365-2249.2012.04676.x.
• [10] Api5 a new cofactor of estrogen receptor alpha involved in breast cancer outcome.Oncotarget. 2017 Apr 20;8(32):52511-52526. doi: 10.18632/oncotarget.17281. eCollection 2017 Aug 8.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples. Data Brief. 2016 Mar 26;7:1052-1057. doi: 10.1016/j.dib.2016.03.069. eCollection 2016 Jun.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [18] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [19] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [25] cDNA microarray analysis of isogenic paclitaxel- and doxorubicin-resistant breast tumor cell lines reveals distinct drug-specific genetic signatures of resistance. Breast Cancer Res Treat. 2006 Mar;96(1):17-39. doi: 10.1007/s10549-005-9026-6. Epub 2005 Dec 2.