Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTY2W6FG)

• DOT Name: Inactive caspase-12 (CASP12)
• Synonyms: CASP-12
• Gene Name: CASP12
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Cardiac disease
  Cervical cancer
  Cervical carcinoma
  Chronic obstructive pulmonary disease
  Depression
  Diabetic kidney disease
  Non-insulin dependent diabetes
  Pancreatitis
  Post-traumatic stress disorder
  Sciatic neuropathy
  Systemic lupus erythematosus
  Type-1 diabetes
  Intracerebral hemorrhage
  Acute liver failure
  Helicoid peripapillary chorioretinal degeneration
  Inflammation
  Nasopharyngeal carcinoma
  Rheumatoid arthritis
• UniProt ID: CASPC_HUMAN
• Pfam ID: PF00619 ; PF00656
• Sequence:
  MADEKPSNGVLVHMVKLLIKTFLDGIFDDLMENNVLNTDEIHLIGKCLKFVVSNAENLVD
  DITETAQIAGKIFREHLWNSKKQLSSDISSDGEREANMPGLNIRNKEFNYLHNRNGSELD
  LLGMRDLLENLGYSVVIKENLTAQEMETALRQFAAHPEHQSSDSTFLVFMSHSILNGICG
  TKHWDQEPDVLHDDTIFEIFNNRNCQSLKDKPKVIIMQACRGNGAGIVWFTTDSGKASAD
  THGRLLQGNICNDAVTKAHVEKDFIAFKSSTPHNVSWRHETNGSVFISQIIYYFREYSWS
  HHLEEIFQKVQHSFETPNILTQLPTIERLSMTRYFYLFPGN
• Function: May function as a negative regulator of inflammatory responses and innate immunity. May reduce cytokine release in response to bacterial lipopolysaccharide during infection. Reduces activation of NF-kappa-B in response to TNF. May lack protease activity (Probable).
• Tissue Specificity: Widely expressed, with highest levels in lung.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Apoptosis (hsa04210)
  NOD-like receptor sig.ling pathway (hsa04621)
  Alzheimer disease (hsa05010)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Hepatitis B (hsa05161)
• BioCyc Pathway: MetaCyc:G66-33181-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Definitive	Therapeutic	[1]
Congestive heart failure	DIS32MEA	Definitive	Therapeutic	[1]
Alzheimer disease	DISF8S70	Strong	Therapeutic	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[3]
Cardiac disease	DISVO1I5	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Therapeutic	[6]
Depression	DIS3XJ69	Strong	Biomarker	[7]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[9]
Pancreatitis	DIS0IJEF	Strong	Biomarker	[10]
Post-traumatic stress disorder	DISHL1EY	Strong	Biomarker	[11]
Sciatic neuropathy	DISMGDKX	Strong	Biomarker	[12]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[13]
Type-1 diabetes	DIS7HLUB	Strong	Biomarker	[14]
Intracerebral hemorrhage	DISC81BT	moderate	Therapeutic	[15]
Acute liver failure	DIS5EZKX	Limited	Therapeutic	[16]
Helicoid peripapillary chorioretinal degeneration	DISFSS5N	Limited	Biomarker	[17]
Inflammation	DISJUQ5T	Limited	Biomarker	[17]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Altered Expression	[18]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Inactive caspase-12 (CASP12).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Inactive caspase-12 (CASP12).	[20]
Ethanol	DMDRQZU	Approved	Ethanol increases the activity of Inactive caspase-12 (CASP12).	[21]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Inactive caspase-12 (CASP12).	[22]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Inactive caspase-12 (CASP12).	[23]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Inactive caspase-12 (CASP12).	[24]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone decreases the expression of Inactive caspase-12 (CASP12).	[25]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the activity of Inactive caspase-12 (CASP12).	[21]
3,7,3',4'-TETRAHYDROXYFLAVONE	DMES906	Investigative	3,7,3',4'-TETRAHYDROXYFLAVONE increases the expression of Inactive caspase-12 (CASP12).	[28]

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 increases the methylation of Inactive caspase-12 (CASP12).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tetrandrine	DMAOJBX	Phase 1	Tetrandrine increases the cleavage of Inactive caspase-12 (CASP12).	[27]
G418	DMKTJBU	Investigative	G418 increases the cleavage of Inactive caspase-12 (CASP12).	[29]

References

• [1] [Salubrinal improves cardiac function in rats with heart failure post myocardial infarction through reducing endoplasmic reticulum stress-associated apoptosis].Zhonghua Xin Xue Guan Bing Za Zhi. 2016 Jun 24;44(6):494-500. doi: 10.3760/cma.j.issn.0253-3758.2016.06.008.
• [2] Involvement of glucose related energy crisis and endoplasmic reticulum stress: Insinuation of streptozotocin induced Alzheimer's like pathology.Cell Signal. 2018 Jan;42:211-226. doi: 10.1016/j.cellsig.2017.10.018. Epub 2017 Nov 7.
• [3] Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1.J Biol Chem. 2006 Oct 6;281(40):30152-65. doi: 10.1074/jbc.M603393200. Epub 2006 Jul 17.
• [4] Activation of caspase-12 at early stage contributes to cardiomyocyte apoptosis in trauma-induced secondary cardiac injury.Sheng Li Xue Bao. 2017 Aug 25;69(4):367-377.
• [5] Analysis of CASP12 diagnostic and prognostic values in cervical cancer based on TCGA database.Biosci Rep. 2019 Dec 20;39(12):BSR20192706. doi: 10.1042/BSR20192706.
• [6] [Resveratrol attenuates endoplasmic reticulum stress and alveolar epithelial apoptosis in a rat model of chronic obstructive pulmonary disease].Zhonghua Jie He He Hu Xi Za Zhi. 2014 Jan;37(1):30-5.
• [7] Quality of life in people aged 65+ in Europe: associated factors and models of social welfare-analysis of data from the SHARE project (Wave 5).Qual Life Res. 2017 Apr;26(4):1059-1070. doi: 10.1007/s11136-016-1436-x. Epub 2016 Oct 20.
• [8] ACE-inhibitor suppresses the apoptosis induced by endoplasmic reticulum stress in renal tubular in experimental diabetic rats.Exp Clin Endocrinol Diabetes. 2009 Jul;117(7):336-44. doi: 10.1055/s-0028-1112148. Epub 2009 Mar 19.
• [9] The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic non-obese type 2 diabetic rats: a differential role of unfolded protein response (UPR) signaling proteins.Int J Biochem Cell Biol. 2013 Feb;45(2):438-47. doi: 10.1016/j.biocel.2012.09.017. Epub 2012 Sep 29.
• [10] Early activation of endoplasmic reticulum stress is associated with arginine-induced acute pancreatitis.Am J Physiol Gastrointest Liver Physiol. 2006 Aug;291(2):G238-45. doi: 10.1152/ajpgi.00471.2005. Epub 2006 Mar 30.
• [11] Single Prolonged Stress induces ATF6 alpha-dependent Endoplasmic reticulum stress and the apoptotic process in medial Frontal Cortex neurons.BMC Neurosci. 2014 Oct 21;15:115. doi: 10.1186/s12868-014-0115-5.
• [12] Evaluation of apoptotic pathways in dorsal root ganglion neurons following peripheral nerve injury.Neuroreport. 2018 Jun 13;29(9):779-785. doi: 10.1097/WNR.0000000000001031.
• [13] The anti-inflammatory CASPASE-12 gene does not influence SLE phenotype in African-Americans.Immunol Lett. 2016 May;173:21-5. doi: 10.1016/j.imlet.2016.03.004. Epub 2016 Mar 10.
• [14] Protective effect of FGF21 on type 1 diabetes-induced testicular apoptotic cell death probably via both mitochondrial- and endoplasmic reticulum stress-dependent pathways in the mouse model.Toxicol Lett. 2013 May 10;219(1):65-76. doi: 10.1016/j.toxlet.2013.02.022. Epub 2013 Mar 7.
• [15] Roles of autophagy and endoplasmic reticulum stress in intracerebral hemorrhage-induced secondary brain injury inrats.CNS Neurosci Ther. 2017 Jul;23(7):554-566. doi: 10.1111/cns.12703. Epub 2017 May 19.
• [16] Hypothyroidism minimizes the effects of acute hepatic failure caused by endoplasmic reticulum stress and redox environment alterations in rats.Acta Histochem. 2015 Oct;117(8):811-9. doi: 10.1016/j.acthis.2015.07.003. Epub 2015 Jul 31.
• [17] CASPASE-12 and rheumatoid arthritis in African-Americans.Immunogenetics. 2014 Apr;66(4):281-5. doi: 10.1007/s00251-014-0762-9. Epub 2014 Feb 11.
• [18] Caspase 12 degrades IB protein and enhances MMP-9 expression in human nasopharyngeal carcinoma cell invasion.Oncotarget. 2017 May 16;8(20):33515-33526. doi: 10.18632/oncotarget.16535.
• [19] Silencing of Hsp27 and Hsp72 in glioma cells as a tool for programmed cell death induction upon temozolomide and quercetin treatment. Toxicol Appl Pharmacol. 2013 Dec 15;273(3):580-9. doi: 10.1016/j.taap.2013.10.003. Epub 2013 Oct 12.
• [20] Endoplasmic reticulum stress contributes to arsenic trioxide-induced apoptosis in drug-sensitive and -resistant leukemia cells. Leuk Res. 2012 Dec;36(12):1526-35. doi: 10.1016/j.leukres.2012.08.018. Epub 2012 Sep 7.
• [21] The resveratrol attenuates ethanol-induced hepatocyte apoptosis via inhibiting ER-related caspase-12 activation and PDE activity in vitro. Alcohol Clin Exp Res. 2014 Mar;38(3):683-93. doi: 10.1111/acer.12311. Epub 2013 Nov 13.
• [22] Combination of all-trans retinoic acid and taxol regressed glioblastoma T98G xenografts in nude mice. Apoptosis. 2007 Nov;12(11):2077-87. doi: 10.1007/s10495-007-0116-2. Epub 2007 Aug 16.
• [23] CDK5-mediated tau accumulation triggers methamphetamine-induced neuronal apoptosis via endoplasmic reticulum-associated degradation pathway. Toxicol Lett. 2018 Aug;292:97-107. doi: 10.1016/j.toxlet.2018.04.027. Epub 2018 Apr 26.
• [24] Resveratrol induced ER expansion and ER caspase-mediated apoptosis in human nasopharyngeal carcinoma cells. Apoptosis. 2014 Mar;19(3):527-41. doi: 10.1007/s10495-013-0945-0.
• [25] Thymoquinone induces apoptosis in bladder cancer cell via endoplasmic reticulum stress-dependent mitochondrial pathway. Chem Biol Interact. 2018 Aug 25;292:65-75. doi: 10.1016/j.cbi.2018.06.013. Epub 2018 Jul 2.
• [26] 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.
• [27] Tetrandrine induces programmed cell death in human oral cancer CAL 27 cells through the reactive oxygen species production and caspase-dependent pathways and associated with beclin-1-induced cell autophagy. Environ Toxicol. 2017 Jan;32(1):329-343. doi: 10.1002/tox.22238. Epub 2016 Jan 29.
• [28] Fisetin-induced apoptosis of human oral cancer SCC-4 cells through reactive oxygen species production, endoplasmic reticulum stress, caspase-, and mitochondria-dependent signaling pathways. Environ Toxicol. 2017 Jun;32(6):1725-1741. doi: 10.1002/tox.22396. Epub 2017 Feb 9.
• [29] Cytochrome c release and endoplasmic reticulum stress are involved in caspase-dependent apoptosis induced by G418. Cell Mol Life Sci. 2004 Jul;61(14):1816-25. doi: 10.1007/s00018-004-4143-7.