Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQYEXL2)

• DOT Name: 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4)
• Synonyms: 6PF-2-K/Fru-2,6-P2ase 4; PFK/FBPase 4; 6PF-2-K/Fru-2,6-P2ase testis-type isozyme
• Gene Name: PFKFB4
• Related Disease:
  Prostate cancer
  Advanced cancer
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Gastric cancer
  Gastric neoplasm
  Glioma
  Hepatocellular carcinoma
  Invasive ductal breast carcinoma
  Metastatic malignant neoplasm
  Metastatic prostate carcinoma
  Pancreatic cancer
  Pancreatic tumour
  Small-cell lung cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Lung cancer
  Melanoma
  Neoplasm
  Adult glioblastoma
  Astrocytoma
  Glioblastoma multiforme
  Prostate carcinoma
• UniProt ID: F264_HUMAN
• EC Number: 2.7.1.105; 3.1.3.46
• Pfam ID: PF01591 ; PF00300
• Sequence:
  MASPRELTQNPLKKIWMPYSNGRPALHACQRGVCMTNCPTLIVMVGLPARGKTYISKKLT
  RYLNWIGVPTREFNVGQYRRDVVKTYKSFEFFLPDNEEGLKIRKQCALAALRDVRRFLSE
  EGGHVAVFDATNTTRERRATIFNFGEQNGYKTFFVESICVDPEVIAANIVQVKLGSPDYV
  NRDSDEATEDFMRRIECYENSYESLDEDLDRDLSYIKIMDVGQSYVVNRVADHIQSRIVY
  YLMNIHVTPRSIYLCRHGESELNLKGRIGGDPGLSPRGREFAKSLAQFISDQNIKDLKVW
  TSQMKRTIQTAEALGVPYEQWKVLNEIDAGVCEEMTYEEIQDNYPLEFALRDQDKYRYRY
  PKGESYEDLVQRLEPVIMELERQENVLVICHQAVMRCLLAYFLDKAAEQLPYLKCPLHTV
  LKLTPVAYGCKVESIFLNVAAVNTHRDRPQNVDISRPPEEALVTVPAHQ
• Function: Synthesis and degradation of fructose 2,6-bisphosphate.
• KEGG Pathway:
  Fructose and mannose metabolism (hsa00051)
  Metabolic pathways (hsa01100)
  AMPK sig.ling pathway (hsa04152)
• Reactome Pathway: Regulation of glycolysis by fructose 2,6-bisphosphate metabolism (R-HSA-9634600)
• BioCyc Pathway: MetaCyc:HS03750-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[1]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[8]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[6]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[6]
Small-cell lung cancer	DISK3LZD	Strong	Biomarker	[9]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[3]
Lung cancer	DISCM4YA	moderate	Altered Expression	[10]
Melanoma	DIS1RRCY	Disputed	Altered Expression	[11]
Neoplasm	DISZKGEW	Disputed	Altered Expression	[12]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[12]
Astrocytoma	DISL3V18	Limited	Biomarker	[12]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[12]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[15]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[17]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[20]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[22]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[23]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[24]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[25]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[15]
Clodronate	DM9Y6X7	Approved	Clodronate decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[15]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[26]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[26]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[27]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[30]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[32]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[34]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[35]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4).	[36]

References

• [1] PFKFB4 Promotes Breast Cancer Metastasis via Induction of Hyaluronan Production in a p38-Dependent Manner.Cell Physiol Biochem. 2018;50(6):2108-2123. doi: 10.1159/000495055. Epub 2018 Nov 9.
• [2] The influence of PFK-II overexpression on neuroblastoma patients' survival may be dependent on the particular isoenzyme expressed, PFKFB3 or PFKFB4.Cancer Cell Int. 2019 Nov 14;19:292. doi: 10.1186/s12935-019-1005-9. eCollection 2019.
• [3] Genetic alteration in phosphofructokinase family promotes growth of muscle-invasive bladder cancer.Int J Biol Markers. 2016 Jul 30;31(3):e286-93. doi: 10.5301/jbm.5000189.
• [4] High expression of metabolic enzyme PFKFB4 is associated with poor prognosis of operable breast cancer.Cancer Cell Int. 2019 Jun 18;19:165. doi: 10.1186/s12935-019-0882-2. eCollection 2019.
• [5] Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer.Nature. 2018 Apr;556(7700):249-254. doi: 10.1038/s41586-018-0018-1. Epub 2018 Apr 3.
• [6] Hypoxic regulation of PFKFB-3 and PFKFB-4 gene expression in gastric and pancreatic cancer cell lines and expression of PFKFB genes in gastric cancers.Acta Biochim Pol. 2006;53(4):789-99. Epub 2006 Dec 4.
• [7] Phosphorylation of PPAR at Ser84 promotes glycolysis and cell proliferation in hepatocellular carcinoma by targeting PFKFB4.Oncotarget. 2016 Nov 22;7(47):76984-76994. doi: 10.18632/oncotarget.12764.
• [8] Functional metabolic screen identifies 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 as an important regulator of prostate cancer cell survival.Cancer Discov. 2012 Apr;2(4):328-43. doi: 10.1158/2159-8290.CD-11-0234. Epub 2012 Mar 22.
• [9] Etk Interaction with PFKFB4 Modulates Chemoresistance of Small-cell Lung Cancer by Regulating Autophagy.Clin Cancer Res. 2018 Feb 15;24(4):950-962. doi: 10.1158/1078-0432.CCR-17-1475. Epub 2017 Dec 5.
• [10] Mechanisms of regulation of PFKFB expression in pancreatic and gastric cancer cells.World J Gastroenterol. 2014 Oct 14;20(38):13705-17. doi: 10.3748/wjg.v20.i38.13705.
• [11] Analysis of Malignant Melanoma Cell Lines Exposed to Hypoxia Reveals the Importance of PFKFB4 Overexpression for Disease Progression.Anticancer Res. 2018 Dec;38(12):6745-6752. doi: 10.21873/anticanres.13044.
• [12] Prognostic Value of PFKFB3 to PFKFB4 mRNA Ratio in Patients With Primary Glioblastoma (IDH-Wildtype).J Neuropathol Exp Neurol. 2019 Sep 1;78(9):865-870. doi: 10.1093/jnen/nlz067.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [14] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [15] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [16] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [17] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [18] 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.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] 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.
• [21] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [22] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [23] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [24] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [25] Chronic ethanol exposure increases goosecoid (GSC) expression in human embryonic carcinoma cell differentiation. J Appl Toxicol. 2014 Jan;34(1):66-75.
• [26] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [29] The BET inhibitor JQ1 selectively impairs tumour response to hypoxia and downregulates CA9 and angiogenesis in triple negative breast cancer. Oncogene. 2017 Jan 5;36(1):122-132. doi: 10.1038/onc.2016.184. Epub 2016 Jun 13.
• [30] 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.
• [31] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [32] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [33] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [34] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [35] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [36] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.