Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8K5PR5)

• DOT Name: Calpain-6 (CAPN6)
• Synonyms: Calpain-like protease X-linked; Calpamodulin; CalpM
• Gene Name: CAPN6
• Related Disease:
  Malignant soft tissue neoplasm
  Sarcoma
  Advanced cancer
  Neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Head-neck squamous cell carcinoma
  Liver cancer
• UniProt ID: CAN6_HUMAN
• Pfam ID: PF00168 ; PF01067 ; PF00648
• Sequence:
  MGPPLKLFKNQKYQELKQECIKDSRLFCDPTFLPENDSLFYNRLLPGKVVWKRPQDICDD
  PHLIVGNISNHQLTQGRLGHKPMVSAFSCLAVQESHWTKTIPNHKEQEWDPQKTEKYAGI
  FHFRFWHFGEWTEVVIDDLLPTINGDLVFSFSTSMNEFWNALLEKAYAKLLGCYEALDGL
  TITDIIVDFTGTLAETVDMQKGRYTELVEEKYKLFGELYKTFTKGGLICCSIESPNQEEQ
  EVETDWGLLKGHTYTMTDIRKIRLGERLVEVFSAEKVYMVRLRNPLGRQEWSGPWSEISE
  EWQQLTASDRKNLGLVMSDDGEFWMSLEDFCRNFHKLNVCRNVNNPIFGRKELESVLGCW
  TVDDDPLMNRSGGCYNNRDTFLQNPQYIFTVPEDGHKVIMSLQQKDLRTYRRMGRPDNYI
  IGFELFKVEMNRKFRLHHLYIQERAGTSTYIDTRTVFLSKYLKKGNYVLVPTMFQHGRTS
  EFLLRIFSEVPVQLRELTLDMPKMSCWNLARGYPKVVTQITVHSAEDLEKKYANETVNPY
  LVIKCGKEEVRSPVQKNTVHAIFDTQAIFYRRTTDIPIIVQVWNSRKFCDQFLGQVTLDA
  DPSDCRDLKSLYLRKKGGPTAKVKQGHISFKVISSDDLTEL
• Function: Microtubule-stabilizing protein that may be involved in the regulation of microtubule dynamics and cytoskeletal organization. May act as a regulator of RAC1 activity through interaction with ARHGEF2 to control lamellipodial formation and cell mobility. Does not seem to have protease activity as it has lost the active site residues.
• Tissue Specificity: Expressed only in placenta.
• Reactome Pathway: Degradation of the extracellular matrix (R-HSA-1474228)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[1]
Sarcoma	DISZDG3U	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[1]
Neoplasm	DISZKGEW	moderate	Biomarker	[1]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[2]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Biomarker	[3]
Liver cancer	DISDE4BI	Limited	Altered Expression	[2]

17 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 Calpain-6 (CAPN6).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Calpain-6 (CAPN6).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Calpain-6 (CAPN6).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Calpain-6 (CAPN6).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Calpain-6 (CAPN6).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Calpain-6 (CAPN6).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Calpain-6 (CAPN6).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Calpain-6 (CAPN6).	[11]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Calpain-6 (CAPN6).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Calpain-6 (CAPN6).	[8]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Calpain-6 (CAPN6).	[13]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Calpain-6 (CAPN6).	[14]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Calpain-6 (CAPN6).	[15]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Calpain-6 (CAPN6).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Calpain-6 (CAPN6).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Calpain-6 (CAPN6).	[18]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Calpain-6 (CAPN6).	[19]

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 Calpain-6 (CAPN6).	[17]

References

• [1] Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence.JCI Insight. 2018 Sep 6;3(17):e121225. doi: 10.1172/jci.insight.121225. eCollection 2018 Sep 6.
• [2] miR-449a promotes liver cancer cell apoptosis by downregulation of Calpain 6 and POU2F1.Oncotarget. 2016 Mar 22;7(12):13491-501. doi: 10.18632/oncotarget.4821.
• [3] Decreased calpain 6 expression is associated with tumorigenesis and poor prognosis in HNSCC.Oncol Lett. 2017 Apr;13(4):2237-2243. doi: 10.3892/ol.2017.5687. Epub 2017 Feb 7.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [7] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [13] 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.
• [14] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [15] 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.
• [16] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [17] 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.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] Persistence of epigenomic effects after recovery from repeated treatment with two nephrocarcinogens. Front Genet. 2018 Dec 3;9:558.