Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2YA5M8)

• DOT Name: Programmed cell death protein 6 (PDCD6)
• Synonyms: Apoptosis-linked gene 2 protein homolog; ALG-2
• Gene Name: PDCD6
• Related Disease:
  Lung adenocarcinoma
  Bladder cancer
  Breast cancer
  Breast neoplasm
  Carcinoma of esophagus
  Colon cancer
  Colon carcinoma
  Congenital hypothyroidism
  Endometriosis
  Esophageal cancer
  Gastric cancer
  Gastric neoplasm
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Melanoma
  Neoplasm of esophagus
  Non-small-cell lung cancer
  Ocular melanoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Uterine fibroids
  Adult glioblastoma
  Advanced cancer
  Breast carcinoma
  Childhood myelodysplastic syndrome
  Epithelial ovarian cancer
  Glioblastoma multiforme
  Myelodysplastic syndrome
  Neoplasm
  Small lymphocytic lymphoma
• UniProt ID: PDCD6_HUMAN
• PDB ID: 2ZN8; 2ZN9; 2ZND; 2ZNE; 2ZRS; 2ZRT; 3AAJ; 3AAK; 3WXA; 5GQQ
• Pfam ID: PF13499
• Sequence:
  MAAYSYRPGPGAGPGPAAGAALPDQSFLWNVFQRVDKDRSGVISDTELQQALSNGTWTPF
  NPVTVRSIISMFDRENKAGVNFSEFTGVWKYITDWQNVFRTYDRDNSGMIDKNELKQALS
  GFGYRLSDQFHDILIRKFDRQGRGQIAFDDFIQGCIVLQRLTDIFRRYDTDQDGWIQVSY
  EQYLSMVFSIV
• Function: Calcium sensor that plays a key role in processes such as endoplasmic reticulum (ER)-Golgi vesicular transport, endosomal biogenesis or membrane repair. Acts as an adapter that bridges unrelated proteins or stabilizes weak protein-protein complexes in response to calcium: calcium-binding triggers exposure of apolar surface, promoting interaction with different sets of proteins thanks to 3 different hydrophobic pockets, leading to translocation to membranes. Involved in ER-Golgi transport by promoting the association between PDCD6IP and TSG101, thereby bridging together the ESCRT-III and ESCRT-I complexes. Together with PEF1, acts as a calcium-dependent adapter for the BCR(KLHL12) complex, a complex involved in ER-Golgi transport by regulating the size of COPII coats. In response to cytosolic calcium increase, the heterodimer formed with PEF1 interacts with, and bridges together the BCR(KLHL12) complex and SEC31 (SEC31A or SEC31B), promoting monoubiquitination of SEC31 and subsequent collagen export, which is required for neural crest specification. Involved in the regulation of the distribution and function of MCOLN1 in the endosomal pathway. Promotes localization and polymerization of TFG at endoplasmic reticulum exit site. Required for T-cell receptor-, Fas-, and glucocorticoid-induced apoptosis. May mediate Ca(2+)-regulated signals along the death pathway: interaction with DAPK1 can accelerate apoptotic cell death by increasing caspase-3 activity. Its role in apoptosis may however be indirect, as suggested by knockout experiments. May inhibit KDR/VEGFR2-dependent angiogenesis; the function involves inhibition of VEGF-induced phosphorylation of the Akt signaling pathway. In case of infection by HIV-1 virus, indirectly inhibits HIV-1 production by affecting viral Gag expression and distribution ; [Isoform 2]: Has a lower Ca(2+) affinity than isoform 1.

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Congenital hypothyroidism	DISL5XVU	Strong	Altered Expression	[6]
Endometriosis	DISX1AG8	Strong	Biomarker	[7]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[8]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[9]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[9]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[9]
Melanoma	DIS1RRCY	Strong	Altered Expression	[10]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[11]
Ocular melanoma	DISOHHFC	Strong	Biomarker	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[2]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[12]
Adult glioblastoma	DISVP4LU	Limited	Altered Expression	[13]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[14]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[3]
Childhood myelodysplastic syndrome	DISMN80I	Limited	Genetic Variation	[15]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[16]
Glioblastoma multiforme	DISK8246	Limited	Altered Expression	[13]
Myelodysplastic syndrome	DISYHNUI	Limited	Genetic Variation	[15]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]
Small lymphocytic lymphoma	DIS30POX	Limited	Genetic Variation	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Programmed cell death protein 6 (PDCD6).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Programmed cell death protein 6 (PDCD6).	[19]
Marinol	DM70IK5	Approved	Marinol increases the expression of Programmed cell death protein 6 (PDCD6).	[20]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Programmed cell death protein 6 (PDCD6).	[21]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Programmed cell death protein 6 (PDCD6).	[22]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Programmed cell death protein 6 (PDCD6).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Programmed cell death protein 6 (PDCD6).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Programmed cell death protein 6 (PDCD6).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Programmed cell death protein 6 (PDCD6).	[25]

References

• [1] Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features.Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10155-60. doi: 10.1073/pnas.0709618105. Epub 2008 Jul 15.
• [2] Prognostic value of PDCD6 polymorphisms and the susceptibility to bladder cancer.Tumour Biol. 2014 Aug;35(8):7547-54. doi: 10.1007/s13277-014-2010-1. Epub 2014 May 3.
• [3] MicroRNA-124-3p directly targets PDCD6 to inhibit metastasis in breast cancer.Oncol Lett. 2018 Jan;15(1):984-990. doi: 10.3892/ol.2017.7358. Epub 2017 Nov 8.
• [4] Highly expressed microRNA-124 inhibits migration and promotes apoptosis of esophageal cancer cells by degrading PDCD6.J BUON. 2019 Mar-Apr;24(2):805-812.
• [5] The apoptosis linked gene ALG-2 is dysregulated in tumors of various origin and contributes to cancer cell viability.Mol Oncol. 2008 Apr;1(4):431-9. doi: 10.1016/j.molonc.2007.08.002. Epub 2007 Aug 19.
• [6] microRNA-124-3p inhibits the progression of congenital hypothyroidism via targeting programmed cell death protein 6.Exp Ther Med. 2018 Jun;15(6):5001-5006. doi: 10.3892/etm.2018.6062. Epub 2018 Apr 13.
• [7] Association between two single nucleotide polymorphisms of PDCD6 gene and increased endometriosis risk.Hum Immunol. 2013 Feb;74(2):215-8. doi: 10.1016/j.humimm.2012.10.025. Epub 2012 Nov 5.
• [8] Identification of prognostic biomarkers in gastric cancer using endoscopic biopsy samples.Cancer Sci. 2008 Nov;99(11):2193-9. doi: 10.1111/j.1349-7006.2008.00935.x. Epub 2008 Jan 11.
• [9] Contribution of programmed cell death 6 genetic variations, gender, and smoking status to lung cancer.Onco Targets Ther. 2019 Aug 9;12:6237-6244. doi: 10.2147/OTT.S205544. eCollection 2019.
• [10] Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma.Biochemistry. 2004 Sep 7;43(35):11175-86. doi: 10.1021/bi048848d.
• [11] Genetic variation in PDCD6 and susceptibility to lung cancer.Asian Pac J Cancer Prev. 2012;13(9):4689-93. doi: 10.7314/apjcp.2012.13.9.4689.
• [12] Variations in the PDCD6 gene are associated with increased uterine leiomyoma risk in the Chinese.Genet Test Mol Biomarkers. 2013 Jul;17(7):524-8. doi: 10.1089/gtmb.2012.0461. Epub 2013 Apr 3.
• [13] ALG2 regulates glioblastoma cell proliferation, migration and tumorigenicity.Biochem Biophys Res Commun. 2017 Apr 29;486(2):300-306. doi: 10.1016/j.bbrc.2017.03.032. Epub 2017 Mar 12.
• [14] ALG-2 participates in recovery of cells after plasma membrane damage by electroporation and digitonin treatment.PLoS One. 2018 Sep 21;13(9):e0204520. doi: 10.1371/journal.pone.0204520. eCollection 2018.
• [15] RUNX1-PDCD6 fusion resulting from a novel t(5;21)(p15;q22) chromosome translocation in myelodysplastic syndrome secondary to chronic lymphocytic leukemia.PLoS One. 2018 Apr 19;13(4):e0196181. doi: 10.1371/journal.pone.0196181. eCollection 2018.
• [16] PDCD6 is an independent predictor of progression free survival in epithelial ovarian cancer.J Transl Med. 2012 Feb 27;10:31. doi: 10.1186/1479-5876-10-31.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [19] 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.
• [20] Single-cell Transcriptome Mapping Identifies Common and Cell-type Specific Genes Affected by Acute Delta9-tetrahydrocannabinol in Humans. Sci Rep. 2020 Feb 26;10(1):3450. doi: 10.1038/s41598-020-59827-1.
• [21] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [22] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [23] Proteomics investigation of protein expression changes in ouabain induced apoptosis in human umbilical vein endothelial cells. J Cell Biochem. 2008 Jun 1;104(3):1054-64. doi: 10.1002/jcb.21691.
• [24] Comparative mechanisms of PAH toxicity by benzo[a]pyrene and dibenzo[def,p]chrysene in primary human bronchial epithelial cells cultured at air-liquid interface. Toxicol Appl Pharmacol. 2019 Sep 15;379:114644.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.