Details of Drug Off-Target (DOT)

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

• DOT Name: Metalloreductase STEAP4 (STEAP4)
• Synonyms: EC 1.16.1.-; Six-transmembrane epithelial antigen of prostate 4; SixTransMembrane protein of prostate 2; Tumor necrosis factor, alpha-induced protein 9
• Gene Name: STEAP4
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Colitis
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Fatty liver disease
  Hepatitis B virus infection
  Hyperinsulinemia
  Inflammatory bowel disease
  Metabolic disorder
  Neoplasm
  Non-alcoholic fatty liver disease
  Obesity
  Prostate carcinoma
  Prostate neoplasm
  Rheumatoid arthritis
  Hepatocellular carcinoma
  Prostate cancer
  Arthritis
  Chronic kidney disease
  Inflammation
  Non-insulin dependent diabetes
• UniProt ID: STEA4_HUMAN
• PDB ID: 6HCY; 6HD1
• EC Number: 1.16.1.-
• Pfam ID: PF03807 ; PF01794
• Sequence:
  MEKTCIDALPLTMNSSEKQETVCIFGTGDFGRSLGLKMLQCGYSVVFGSRNPQKTTLLPS
  GAEVLSYSEAAKKSGIIIIAIHREHYDFLTELTEVLNGKILVDISNNLKINQYPESNAEY
  LAHLVPGAHVVKAFNTISAWALQSGALDASRQVFVCGNDSKAKQRVMDIVRNLGLTPMDQ
  GSLMAAKEIEKYPLQLFPMWRFPFYLSAVLCVFLFFYCVIRDVIYPYVYEKKDNTFRMAI
  SIPNRIFPITALTLLALVYLPGVIAAILQLYRGTKYRRFPDWLDHWMLCRKQLGLVALGF
  AFLHVLYTLVIPIRYYVRWRLGNLTVTQAILKKENPFSTSSAWLSDSYVALGILGFFLFV
  LLGITSLPSVSNAVNWREFRFVQSKLGYLTLILCTAHTLVYGGKRFLSPSNLRWYLPAAY
  VLGLIIPCTVLVIKFVLIMPCVDNTLTRIRQGWERNSKH
• Function: Integral membrane protein that functions as a NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane. Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate. Can also reduce Cu(2+) to Cu(1+). Plays a role in systemic metabolic homeostasis, integrating inflammatory and metabolic responses. Associated with obesity and insulin-resistance. Involved in inflammatory arthritis, through the regulation of inflammatory cytokines. Inhibits anchorage-independent cell proliferation.
• Tissue Specificity: Ubiquitous. Highly expressed in adipose tissue. Expressed in placenta, lung, heart and prostate. Detected at lower levels in liver, skeletal muscle, pancreas, testis and small intestine. Highly expressed in joints of patients with rheumatoid arthritis and localized with CD68 cells, a marker for macrophages.

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[2]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[2]
Colitis	DISAF7DD	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[6]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[3]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[8]
Obesity	DIS47Y1K	Strong	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[12]
Prostate cancer	DISF190Y	moderate	Biomarker	[10]
Arthritis	DIST1YEL	Limited	Biomarker	[11]
Chronic kidney disease	DISW82R7	Limited	Altered Expression	[13]
Inflammation	DISJUQ5T	Limited	Altered Expression	[13]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Altered Expression	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Metalloreductase STEAP4 (STEAP4).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Metalloreductase STEAP4 (STEAP4).	[15]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Metalloreductase STEAP4 (STEAP4).	[16]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Metalloreductase STEAP4 (STEAP4).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Metalloreductase STEAP4 (STEAP4).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Metalloreductase STEAP4 (STEAP4).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Metalloreductase STEAP4 (STEAP4).	[19]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Metalloreductase STEAP4 (STEAP4).	[20]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Metalloreductase STEAP4 (STEAP4).	[21]

References

• [1] Long-term exposure of MCF-7 breast cancer cells to ethanol stimulates oncogenic features.Int J Oncol. 2017 Jan;50(1):49-65. doi: 10.3892/ijo.2016.3800. Epub 2016 Dec 9.
• [2] Stamp2 controls macrophage inflammation through nicotinamide adenine dinucleotide phosphate homeostasis and protects against atherosclerosis.Cell Metab. 2012 Jul 3;16(1):81-9. doi: 10.1016/j.cmet.2012.05.009. Epub 2012 Jun 14.
• [3] Quantitative proteomics identifies STEAP4 as a critical regulator of mitochondrial dysfunction linking inflammation and colon cancer.Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):E9608-E9617. doi: 10.1073/pnas.1712946114. Epub 2017 Oct 23.
• [4] Hepatic STAMP2 alleviates high fat diet-induced hepatic steatosis and insulin resistance.J Hepatol. 2015 Aug;63(2):477-85. doi: 10.1016/j.jhep.2015.01.025. Epub 2015 Jan 31.
• [5] Hepatic STAMP2 decreases hepatitis B virus X protein-associated metabolic deregulation.Exp Mol Med. 2012 Oct 31;44(10):622-32. doi: 10.3858/emm.2012.44.10.071.
• [6] Proadipogenic effects of lactoferrin in human subcutaneous and visceral preadipocytes.J Nutr Biochem. 2011 Dec;22(12):1143-9. doi: 10.1016/j.jnutbio.2010.09.015. Epub 2011 Feb 4.
• [7] STAMP2 is required for human adipose-derived stem cell differentiation and adipocyte-facilitated prostate cancer growth in vivo.Oncotarget. 2016 Aug 9;8(54):91817-91827. doi: 10.18632/oncotarget.11131. eCollection 2017 Nov 3.
• [8] Cilostazol Improves HFD-Induced Hepatic Steatosis by Upregulating Hepatic STAMP2 Expression through AMPK.Mol Pharmacol. 2018 Dec;94(6):1401-1411. doi: 10.1124/mol.118.113217. Epub 2018 Oct 26.
• [9] STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation.Endocrine. 2017 Jun;56(3):528-537. doi: 10.1007/s12020-017-1297-2. Epub 2017 Apr 12.
• [10] Utilisation of the STEAP protein family in a diagnostic setting may provide a more comprehensive prognosis of prostate cancer.PLoS One. 2019 Aug 8;14(8):e0220456. doi: 10.1371/journal.pone.0220456. eCollection 2019.
• [11] Clinical and functional significance of STEAP4-splice variant in CD14(+) monocytes in patients with rheumatoid arthritis.Clin Exp Immunol. 2018 Mar;191(3):338-348. doi: 10.1111/cei.13076. Epub 2017 Nov 16.
• [12] Long noncoding RNA SchLAH suppresses metastasis of hepatocellular carcinoma through interacting with fused in sarcoma.Cancer Sci. 2017 Apr;108(4):653-662. doi: 10.1111/cas.13200. Epub 2017 Apr 17.
• [13] Effect of Omega-3 Fatty Acid on STAMP2 Expression in the Heart and Kidney of 5/6 Nephrectomy Rat Model.Mar Drugs. 2018 Oct 23;16(11):398. doi: 10.3390/md16110398.
• [14] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [15] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [16] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [17] Adipogenic Effects and Gene Expression Profiling of Firemaster? 550 Components in Human Primary Preadipocytes. Environ Health Perspect. 2017 Sep 14;125(9):097013. doi: 10.1289/EHP1318.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] Label-free quantitative proteomic analysis identifies the oncogenic role of FOXA1 in BaP-transformed 16HBE cells. Toxicol Appl Pharmacol. 2020 Sep 15;403:115160. doi: 10.1016/j.taap.2020.115160. Epub 2020 Jul 25.
• [20] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [21] Copper signaling axis as a target for prostate cancer therapeutics. Cancer Res. 2014 Oct 15;74(20):5819-31. doi: 10.1158/0008-5472.CAN-13-3527.