Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAQ2S8R)

• DOT Name: Pannexin-2 (PANX2)
• Gene Name: PANX2
• Related Disease:
  Crohn disease
  Epilepsy
  Fleck corneal dystrophy
  Glioma
  Ulcerative colitis
  Clear cell renal carcinoma
  Kidney cancer
  Renal carcinoma
  Renal cell carcinoma
  Type-1 diabetes
• UniProt ID: PANX2_HUMAN
• PDB ID: 7XLB; 8F7C
• Pfam ID: PF00876
• Sequence:
  MHHLLEQSADMATALLAGEKLRELILPGAQDDKAGALAALLLQLKLELPFDRVVTIGTVL
  VPILLVTLVFTKNFAEEPIYCYTPHNFTRDQALYARGYCWTELRDALPGVDASLWPSLFE
  HKFLPYALLAFAAIMYVPALGWEFLASTRLTSELNFLLQEIDNCYHRAAEGRAPKIEKQI
  QSKGPGITEREKREIIENAEKEKSPEQNLFEKYLERRGRSNFLAKLYLARHVLILLLSAV
  PISYLCTYYATQKQNEFTCALGASPDGAAGAGPAVRVSCKLPSVQLQRIIAGVDIVLLCV
  MNLIILVNLIHLFIFRKSNFIFDKLHKVGIKTRRQWRRSQFCDINILAMFCNENRDHIKS
  LNRLDFITNESDLMYDNVVRQLLAALAQSNHDATPTVRDSGVQTVDPSANPAEPDGAAEP
  PVVKRPRKKMKWIPTSNPLPQPFKEPLAIMRVENSKAEKPKPARRKTATDTLIAPLLDRS
  AHHYKGGGGDPGPGPAPAPAPPPAPDKKHARHFSLDVHPYILGTKKAKAEAVPAALPASR
  SQEGGFLSQAEDCGLGLAPAPIKDAPLPEKEIPYPTEPARAGLPSGGPFHVRSPPAAPAV
  APLTPASLGKAEPLTILSRNATHPLLHINTLYEAREEEDGGPRLPQDVGDLIAIPAPQQI
  LIATFDEPRTVVSTVEF
• Function: Ion channel with a slight anion preference. Also able to release ATP. Plays a role in regulating neurogenesis and apoptosis in keratinocytes.
• Reactome Pathway: Electric Transmission Across Gap Junctions (R-HSA-112303)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[1]
Epilepsy	DISBB28L	Strong	Biomarker	[2]
Fleck corneal dystrophy	DISERQJ1	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	moderate	Altered Expression	[4]
Kidney cancer	DISBIPKM	moderate	Biomarker	[4]
Renal carcinoma	DISER9XT	moderate	Biomarker	[4]
Renal cell carcinoma	DISQZ2X8	moderate	Altered Expression	[4]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[5]

3 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 Pannexin-2 (PANX2).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Pannexin-2 (PANX2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Pannexin-2 (PANX2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Pannexin-2 (PANX2).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Pannexin-2 (PANX2).	[9]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Pannexin-2 (PANX2).	[10]
Marinol	DM70IK5	Approved	Marinol increases the expression of Pannexin-2 (PANX2).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Pannexin-2 (PANX2).	[12]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Pannexin-2 (PANX2).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Pannexin-2 (PANX2).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Pannexin-2 (PANX2).	[16]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of Pannexin-2 (PANX2).	[17]

References

• [1] Pannexin-2 is expressed in the human colon with extensive localization in the enteric nervous system.Neurogastroenterol Motil. 2015 May;27(5):672-83. doi: 10.1111/nmo.12541. Epub 2015 Mar 14.
• [2] Expression of pannexin 1 and 2 in cortical lesions from intractable epilepsy patients with focal cortical dysplasia.Oncotarget. 2017 Jan 24;8(4):6883-6895. doi: 10.18632/oncotarget.14317.
• [3] MicroRNA-423-3p promotes glioma growth by targeting PANX2.Oncol Lett. 2018 Jul;16(1):179-188. doi: 10.3892/ol.2018.8636. Epub 2018 May 4.
• [4] The Expression Patterns of FAM83H and PANX2 Are Associated With Shorter Survival of Clear Cell Renal Cell Carcinoma Patients.Front Oncol. 2019 Jan 22;9:14. doi: 10.3389/fonc.2019.00014. eCollection 2019.
• [5] Pannexin-2-deficiency sensitizes pancreatic -cells to cytokine-induced apoptosis invitro and impairs glucose tolerance invivo.Mol Cell Endocrinol. 2017 Jun 15;448:108-121. doi: 10.1016/j.mce.2017.04.001. Epub 2017 Apr 5.
• [6] 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.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [12] 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.
• [13] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [14] 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.
• [15] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.