Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVS2GXA)

• DOT Name: Protein CIP2A (CIP2A)
• Synonyms: Cancerous inhibitor of PP2A; p90 autoantigen
• Gene Name: CIP2A
• Related Disease:
  Estrogen-receptor positive breast cancer
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Melanoma
  Acute myelogenous leukaemia
  Adenocarcinoma
  Alzheimer disease
  Benign prostatic hyperplasia
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cervical cancer
  Cervical carcinoma
  Chronic obstructive pulmonary disease
  Cognitive impairment
  Colorectal carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Neuroblastoma
  Non-small-cell lung cancer
  Pancreatic cancer
  Polyarteritis nodosa
  Prostate carcinoma
  Renal cell carcinoma
  Rheumatoid arthritis
  rubella
  Stomach cancer
  Triple negative breast cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Vasculitis due to ADA2 deficiency
  Colon cancer
  Colon carcinoma
  Osteosarcoma
  Prostate cancer
  Carcinoma
  Epithelial ovarian cancer
  leukaemia
  Leukemia
  Oral cancer
  Oral cavity carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Plasma cell myeloma
  Squamous cell carcinoma
• UniProt ID: CIP2A_HUMAN
• PDB ID: 5UFL
• Pfam ID: PF21044
• Sequence:
  MDSTACLKSLLLTVSQYKAVKSEANATQLLRHLEVISGQKLTRLFTSNQILTSECLSCLV
  ELLEDPNISASLILSIIGLLSQLAVDIETRDCLQNTYNLNSVLAGVVCRSSHTDSVFLQC
  IQLLQKLTYNVKIFYSGANIDELITFLIDHIQSSEDELKMPCLGLLANLCRHNLSVQTHI
  KTLSNVKSFYRTLITLLAHSSLTVVVFALSILSSLTLNEEVGEKLFHARNIHQTFQLIFN
  ILINGDGTLTRKYSVDLLMDLLKNPKIADYLTRYEHFSSCLHQVLGLLNGKDPDSSSKVL
  ELLLAFCSVTQLRHMLTQMMFEQSPPGSATLGSHTKCLEPTVALLRWLSQPLDGSENCSV
  LALELFKEIFEDVIDAANCSSADRFVTLLLPTILDQLQFTEQNLDEALTRKKCERIAKAI
  EVLLTLCGDDTLKMHIAKILTTVKCTTLIEQQFTYGKIDLGFGTKVADSELCKLAADVIL
  KTLDLINKLKPLVPGMEVSFYKILQDPRLITPLAFALTSDNREQVQSGLRILLEAAPLPD
  FPALVLGESIAANNAYRQQETEHIPRKMPWQSSNHSFPTSIKCLTPHLKDGVPGLNIEEL
  IEKLQSGMVVKDQICDVRISDIMDVYEMKLSTLASKESRLQDLLETKALALAQADRLIAQ
  HRCQRTQAETEARTLASMLREVERKNEELSVLLKAQQVESERAQSDIEHLFQHNRKLESV
  AEEHEILTKSYMELLQRNESTEKKNKDLQITCDSLNKQIETVKKLNESLKEQNEKSIAQL
  IEKEEQRKEVQNQLVDREHKLANLHQKTKVQEEKIKTLQKEREDKEETIDILRKELSRTE
  QIRKELSIKASSLEVQKAQLEGRLEEKESLVKLQQEELNKHSHMIAMIHSLSGGKINPET
  VNLSI
• Function: Acts as an inhibitor of protein phosphatase PP2A. Promotes anchorage-independent cell growth and tumor formation by preventing dephosphorylation of MYC, thereby stabilizing MYC in human malignancies. Together with TOPBP1, plays an essential role in the response to genome instability generated by the presence of acentric chromosome fragments derived from shattered chromosomes within micronuclei. Micronuclei, which are frequently found in cancer cells, consist of chromatin surrounded by their own nuclear membrane: following breakdown of the micronuclear envelope, a process associated with chromothripsis, the CIP2A-TOPBP1 complex tethers chromosome fragments during mitosis to ensure clustered segregation of the fragments to a single daughter cell nucleus, facilitating re-ligation with limited chromosome scattering and loss.
• Tissue Specificity: Expressed at low levels in most of the tissues. Overexpressed in head-and-neck squamous cell carcinomas (HNSCC). Present in liver cancer cells (at protein level).

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Estrogen-receptor positive breast cancer	DIS1H502	Definitive	Altered Expression	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[2]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[3]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[3]
Melanoma	DIS1RRCY	Definitive	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[5]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Biomarker	[7]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[8]
Bladder cancer	DISUHNM0	Strong	Biomarker	[9]
Breast cancer	DIS7DPX1	Strong	Biomarker	[10]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[10]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[11]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[11]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[12]
Cognitive impairment	DISH2ERD	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[13]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[14]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[15]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[16]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[17]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[19]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[20]
Polyarteritis nodosa	DISRQ5X8	Strong	Altered Expression	[17]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[21]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[23]
rubella	DISXUI9P	Strong	Biomarker	[24]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[14]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[25]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[9]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[9]
Vasculitis due to ADA2 deficiency	DIS1UHPY	Strong	Altered Expression	[17]
Colon cancer	DISVC52G	moderate	Altered Expression	[26]
Colon carcinoma	DISJYKUO	moderate	Altered Expression	[26]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[27]
Prostate cancer	DISF190Y	Disputed	Biomarker	[21]
Carcinoma	DISH9F1N	Limited	Altered Expression	[28]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[28]
leukaemia	DISS7D1V	Limited	Biomarker	[10]
Leukemia	DISNAKFL	Limited	Biomarker	[10]
Oral cancer	DISLD42D	Limited	Altered Expression	[29]
Oral cavity carcinoma	DISZXMVL	Limited	Altered Expression	[30]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[28]
Ovarian neoplasm	DISEAFTY	Limited	Altered Expression	[28]
Plasma cell myeloma	DIS0DFZ0	Limited	Biomarker	[31]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[32]

16 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 Protein CIP2A (CIP2A).	[33]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein CIP2A (CIP2A).	[34]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Protein CIP2A (CIP2A).	[35]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein CIP2A (CIP2A).	[36]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein CIP2A (CIP2A).	[37]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein CIP2A (CIP2A).	[38]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Protein CIP2A (CIP2A).	[39]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein CIP2A (CIP2A).	[40]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein CIP2A (CIP2A).	[41]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein CIP2A (CIP2A).	[40]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Protein CIP2A (CIP2A).	[42]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of Protein CIP2A (CIP2A).	[43]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein CIP2A (CIP2A).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein CIP2A (CIP2A).	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein CIP2A (CIP2A).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein CIP2A (CIP2A).	[47]

References

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• [5] Arpp19 Promotes Myc and Cip2a Expression and Associates with Patient Relapse in Acute Myeloid Leukemia.Cancers (Basel). 2019 Nov 11;11(11):1774. doi: 10.3390/cancers11111774.
• [6] Prognostic Significance of CIP2A in Esophagogastric Junction Adenocarcinoma: A Study of 65 Patients and a Meta-Analysis.Dis Markers. 2019 Aug 22;2019:2312439. doi: 10.1155/2019/2312439. eCollection 2019.
• [7] CIP2A-promoted astrogliosis induces AD-like synaptic degeneration and cognitive deficits.Neurobiol Aging. 2019 Mar;75:198-208. doi: 10.1016/j.neurobiolaging.2018.11.023. Epub 2018 Dec 6.
• [8] CIP2A mediates prostate cancer progression via the c-Myc signaling pathway.Tumour Biol. 2015 Jun;36(6):4777-83. doi: 10.1007/s13277-015-3129-4. Epub 2015 Jan 31.
• [9] CIP2A depletion potentiates the chemosensitivity of cisplatin by inducing increased apoptosis in bladder cancer cells.Oncol Rep. 2018 Nov;40(5):2445-2454. doi: 10.3892/or.2018.6641. Epub 2018 Aug 10.
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• [11] Feedback between E2F1 and CIP2A regulated by human papillomavirus E7 in cervical cancer: implications for prognosis.Am J Transl Res. 2017 May 15;9(5):2327-2339. eCollection 2017.
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• [16] Protein phosphatase 2A (PP2A) inhibitor CIP2A indicates resistance to radiotherapy in rectal cancer.Cancer Med. 2018 Mar;7(3):698-706. doi: 10.1002/cam4.1361. Epub 2018 Feb 14.
• [17] Inhibition of CIP2A attenuates tumor progression by inducing cell cycle arrest and promoting cellular senescence in hepatocellular carcinoma.Biochem Biophys Res Commun. 2018 Jan 8;495(2):1807-1814. doi: 10.1016/j.bbrc.2017.11.124. Epub 2017 Nov 21.
• [18] Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma.Proc Natl Acad Sci U S A. 2018 Jul 31;115(31):E7351-E7360. doi: 10.1073/pnas.1800039115. Epub 2018 Jul 18.
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• [20] CIP2A down regulation enhances the sensitivity of pancreatic cancer cells to gemcitabine.Oncotarget. 2016 Mar 22;7(12):14831-40. doi: 10.18632/oncotarget.7447.
• [21] Polyphyllin I inhibits invasion and epithelial-mesenchymal transition via CIP2A/PP2A/ERK signaling in prostate cancer.Int J Oncol. 2018 Sep;53(3):1279-1288. doi: 10.3892/ijo.2018.4464. Epub 2018 Jun 29.
• [22] CIP2A Promotes Proliferation, Invasion and Chemoresistance to Cisplatin in Renal Cell Carcinoma.J Cancer. 2018 Oct 17;9(21):4029-4038. doi: 10.7150/jca.25005. eCollection 2018.
• [23] CIP2A facilitates apoptotic resistance of fibroblast-like synoviocytes in rheumatoid arthritis independent of c-Myc expression.Rheumatol Int. 2013 Sep;33(9):2241-8. doi: 10.1007/s00296-013-2711-6. Epub 2013 Mar 2.
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• [26] ER stress-related ATF6 upregulates CIP2A and contributes to poor prognosis of colon cancer.Mol Oncol. 2018 Oct;12(10):1706-1717. doi: 10.1002/1878-0261.12365. Epub 2018 Aug 20.
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• [28] CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis.Tumour Biol. 2012 Dec;33(6):2299-306. doi: 10.1007/s13277-012-0492-2. Epub 2012 Aug 25.
• [29] CIP2A overexpression in Taiwanese oral cancer patients.Cancer Manag Res. 2019 Apr 5;11:2589-2594. doi: 10.2147/CMAR.S201154. eCollection 2019.
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• [31] CIP2A regulates proliferation and apoptosis of multiple myeloma cells.Mol Med Rep. 2016 Sep;14(3):2705-9. doi: 10.3892/mmr.2016.5553. Epub 2016 Jul 27.
• [32] High expression of CIP2A protein is associated with tumor aggressiveness in stage I-III NSCLC and correlates with poor prognosis.Onco Targets Ther. 2017 Dec 12;10:5907-5914. doi: 10.2147/OTT.S148250. eCollection 2017.
• [33] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
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• [35] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
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• [38] 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.
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• [41] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [42] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [43] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [44] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [46] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [47] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.