Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF191LZ)

• DOT Name: Calcium-activated chloride channel regulator 2 (CLCA2)
• Synonyms: EC 3.4.-.-; Calcium-activated chloride channel family member 2; hCLCA2; Calcium-activated chloride channel protein 3; CaCC-3; hCaCC-3
• Gene Name: CLCA2
• Related Disease:
  Adenocarcinoma
  Hepatic encephalopathy
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Squamous cell carcinoma
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Leukemia
  Lung neoplasm
  Metastatic malignant neoplasm
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Crohn disease
  Heart arrhythmia
  Advanced cancer
  Breast cancer
  Breast neoplasm
• UniProt ID: CLCA2_HUMAN
• EC Number: 3.4.-.-
• Pfam ID: PF08434
• Sequence:
  MTQRSIAGPICNLKFVTLLVALSSELPFLGAGVQLQDNGYNGLLIAINPQVPENQNLISN
  IKEMITEASFYLFNATKRRVFFRNIKILIPATWKANNNSKIKQESYEKANVIVTDWYGAH
  GDDPYTLQYRGCGKEGKYIHFTPNFLLNDNLTAGYGSRGRVFVHEWAHLRWGVFDEYNND
  KPFYINGQNQIKVTRCSSDITGIFVCEKGPCPQENCIISKLFKEGCTFIYNSTQNATASI
  MFMQSLSSVVEFCNASTHNQEAPNLQNQMCSLRSAWDVITDSADFHHSFPMNGTELPPPP
  TFSLVQAGDKVVCLVLDVSSKMAEADRLLQLQQAAEFYLMQIVEIHTFVGIASFDSKGEI
  RAQLHQINSNDDRKLLVSYLPTTVSAKTDISICSGLKKGFEVVEKLNGKAYGSVMILVTS
  GDDKLLGNCLPTVLSSGSTIHSIALGSSAAPNLEELSRLTGGLKFFVPDISNSNSMIDAF
  SRISSGTGDIFQQHIQLESTGENVKPHHQLKNTVTVDNTVGNDTMFLVTWQASGPPEIIL
  FDPDGRKYYTNNFITNLTFRTASLWIPGTAKPGHWTYTLNNTHHSLQALKVTVTSRASNS
  AVPPATVEAFVERDSLHFPHPVMIYANVKQGFYPILNATVTATVEPETGDPVTLRLLDDG
  AGADVIKNDGIYSRYFFSFAANGRYSLKVHVNHSPSISTPAHSIPGSHAMYVPGYTANGN
  IQMNAPRKSVGRNEEERKWGFSRVSSGGSFSVLGVPAGPHPDVFPPCKIIDLEAVKVEEE
  LTLSWTAPGEDFDQGQATSYEIRMSKSLQNIQDDFNNAILVNTSKRNPQQAGIREIFTFS
  PQISTNGPEHQPNGETHESHRIYVAIRAMDRNSLQSAVSNIAQAPLFIPPNSDPVPARDY
  LILKGVLTAMGLIGIICLIIVVTHHTLSRKKRADKKENGTKLL
• Function: Plays a role in modulating chloride current across the plasma membrane in a calcium-dependent manner, and cell adhesion. Involved in basal cell adhesion and/or stratification of squamous epithelia. May act as a tumor suppressor in breast and colorectal cancer. Plays a key role for cell adhesion in the beginning stages of lung metastasis via the binding to ITGB4.
• Tissue Specificity: Expressed in cornea, skin, vagina, esophagus, and larynx (at protein level). Expressed in trachea and mammary gland. Weakly expressed in testis and kidney. Highly expressed in corneal epithelium, colon and trachea. Moderately expressed in brain, urogenital organs, bladder, uterus and prostate. Highly expressed in tissues containing stratified epithelium including cornea, esophagus, larynx, skin and vagina than those tissues which contain only epithelial monolayers. Expressed in normal breast epithelium but not in breast cancer. Highly expressed during epithelial stratification. Expressed in endothelial cells of lung. Expressed selectively in endothelia of small pulmonary arteries, arterioles, and subpleural and interlobular venules.
• KEGG Pathway:
  Renin secretion (hsa04924)
  Pancreatic secretion (hsa04972)
• Reactome Pathway: Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Definitive	Biomarker	[1]
Hepatic encephalopathy	DISEAKAN	Definitive	Genetic Variation	[2]
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[1]
Lung cancer	DISCM4YA	Definitive	Biomarker	[3]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[1]
Squamous cell carcinoma	DISQVIFL	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Leukemia	DISNAKFL	Strong	Biomarker	[7]
Lung neoplasm	DISVARNB	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[8]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[9]
Heart arrhythmia	DISLKUNL	Moderate	Autosomal dominant	[10]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[4]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Calcium-activated chloride channel regulator 2 (CLCA2).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Calcium-activated chloride channel regulator 2 (CLCA2).	[12]
Lucanthone	DMZLBUO	Approved	Lucanthone increases the expression of Calcium-activated chloride channel regulator 2 (CLCA2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Calcium-activated chloride channel regulator 2 (CLCA2).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Calcium-activated chloride channel regulator 2 (CLCA2).	[15]

References

• [1] CLCA2 as a novel immunohistochemical marker for differential diagnosis of squamous cell carcinoma from adenocarcinoma of the lung.Dis Markers. 2014;2014:619273. doi: 10.1155/2014/619273. Epub 2014 Dec 7.
• [2] Variations in the promoter region of the glutaminase gene and the development of hepatic encephalopathy in patients with cirrhosis: a cohort study.Ann Intern Med. 2010 Sep 7;153(5):281-8. doi: 10.7326/0003-4819-153-5-201009070-00002.
• [3] Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents.Oncotarget. 2017 Mar 21;8(12):18885-18900. doi: 10.18632/oncotarget.13806.
• [4] Along with its favorable prognostic role, CLCA2 inhibits growth and metastasis of nasopharyngeal carcinoma cells via inhibition of FAK/ERK signaling.J Exp Clin Cancer Res. 2018 Feb 20;37(1):34. doi: 10.1186/s13046-018-0692-8.
• [5] Prognostic value of chloride channel accessory mRNA expression in colon cancer.Oncol Lett. 2019 Sep;18(3):2967-2976. doi: 10.3892/ol.2019.10615. Epub 2019 Jul 15.
• [6] Expression of the Ca2+-activated chloride channel genes CLCA1 and CLCA2 is downregulated in human colorectal cancer.DNA Cell Biol. 2001 Jun;20(6):331-8. doi: 10.1089/10445490152122442.
• [7] CLCA2, a novel RUNX1 partner gene in a therapy-related leukemia with t(1;21)(p22;q22).Cancer Genet Cytogenet. 2010 Oct 15;202(2):94-100. doi: 10.1016/j.cancergencyto.2010.07.116.
• [8] CLCA2 epigenetic regulation by CTBP1, HDACs, ZEB1, EP300 and miR-196b-5p impacts prostate cancer cell adhesion and EMT in metabolic syndrome disease.Int J Cancer. 2018 Aug 15;143(4):897-906. doi: 10.1002/ijc.31379. Epub 2018 Mar 30.
• [9] Identification of risk loci for Crohn's disease phenotypes using a genome-wide association study.Gastroenterology. 2015 Apr;148(4):794-805. doi: 10.1053/j.gastro.2014.12.030. Epub 2014 Dec 31.
• [10] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] 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.
• [13] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [14] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [15] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.