title: Developmental regulation and induction of cytochrome P450 2W1, an enzyme expressed in colon tumors.
abstract: Cytochrome P450 2W1 (CYP2W1) is expressed predominantly in colorectal and also in hepatic tumors, whereas the levels are insignificant in the corresponding normal human adult tissues. CYP2W1 has been proposed as an attractive target for colorectal cancer (CRC) therapy by exploiting its ability to activate duocarmycin prodrugs to cytotoxic metabolites. However, its endogenous function, regulation and developmental pattern of expression remain unexplored. Here we report the CYP2W1 developmental expression in the murine and human gastrointestinal tissues. The gene expression in the colon and small intestine commence at early stages of embryonic life and is completely silenced shortly after the birth. Immunohistochemical analysis of human fetal colon revealed that CYP2W1 expression is restricted to the crypt cells. The silencing of CYP2W1 after birth correlates with the increased methylation of CpG-rich regions in both murine and human CYP2W1 genes. Analysis of CYP2W1 expression in the colon adenocarcinoma cell line HCC2998 revealed that the gene expression can be induced by e.g. the antitumor agent imatinib, linoleic acid and its derivatives. The imatinib mediated induction of CYP2W1 suggests an adjuvant therapy to treatment with duocarmycins that thus would involve induction of tumor CYP2W1 levels followed by the CYP2W1 activated duocarmycin prodrugs. Taken together these data strongly support further exploration of CYP2W1 as a specific drug target in CRC.
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Choong
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Persson
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Virding
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Inger
authors.initials: I
authors.lastname: Johansson
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Souren
authors.initials: S
authors.lastname: Mkrtchian
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism*; D000072467:Cytochrome P450 Family 2; D044127:Epigenesis, Genetic; D041981:Gastrointestinal Tract / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; C509336:CYP2W1 protein, human; C000606258:CYP2W1 protein, mouse; D000072467:Cytochrome P450 Family 2
references.citation: Clin Colorectal Cancer. 2007 Nov;6(10):683-90
references.pmid: 18039421
references.citation: Toxicol In Vitro. 2001 Aug-Oct;15(4-5):373-8
references.pmid: 11566566
references.citation: Cancer Res. 2005 Oct 1;65(19):8715-22
references.pmid: 16204040
references.citation: Chem Res Toxicol. 2012 Aug 20;25(8):1740-51
references.pmid: 22734839
references.citation: Oncogene. 2006 Apr 20;25(17):2546-57
references.pmid: 16331256
references.citation: Curr Top Dev Biol. 2005;67:85-133
references.pmid: 15949532
references.citation: Drug Metab Dispos. 2007 Jun;35(6):987-94
references.pmid: 17325023
references.citation: Genome Res. 2008 Sep;18(9):1518-29
references.pmid: 18577705
references.citation: Br J Cancer. 1992 Nov;66(5):867-9
references.pmid: 1419629
references.citation: BMC Cancer. 2009 Jun 16;9:187
references.pmid: 19531241
references.citation: Eur J Surg Oncol. 2012 Jan;38(1):16-24
references.pmid: 22079259
references.citation: J Zhejiang Univ Sci B. 2013 Feb;14(2):115-23
references.pmid: 23365010
references.citation: Pharmacogenomics. 2013 Oct;14(13):1615-22
references.pmid: 24088132
references.citation: Biochim Biophys Acta. 2013 Nov;1829(11):1161-74
references.pmid: 23938249
references.citation: Drug Metabol Drug Interact. 2012 Jan 31;27(1):3-8
references.pmid: 22718620
references.citation: Semin Reprod Endocrinol. 1999;17(3):275-90
references.pmid: 10797946
references.citation: Oncotarget. 2012 Apr;3(4):462-74
references.pmid: 22577155
references.citation: Arch Biochem Biophys. 2005 Apr 1;436(1):50-61
references.pmid: 15752708
references.citation: Curr Med Chem. 2014;21(5):519-52
references.pmid: 24083611
references.citation: Eur J Cancer. 2009 Mar;45(4):705-12
references.pmid: 19118998
references.citation: Cancer Res. 1997 Jul 15;57(14):3026-31
references.pmid: 9230218
references.citation: Biopharm Drug Dispos. 2008 Mar;29(2):103-18
references.pmid: 18188833
references.citation: BMC Genomics. 2014 Aug 26;15:716
references.pmid: 25163507
references.citation: Nat Rev Cancer. 2007 Apr;7(4):246-55
references.pmid: 17384580
references.citation: Chem Phys Lipids. 2013 Oct-Nov;175-176:27-32
references.pmid: 23954748
references.citation: Biochem Pharmacol. 2010 Jan 15;79(2):261-9
references.pmid: 19682433
references.citation: Biochem Pharmacol. 2004 Apr 1;67(7):1249-58
references.pmid: 15013840
references.citation: Clin Cancer Res. 2013 Jun 1;19(11):2952-61
references.pmid: 23589180
references.citation: Pharmacogenomics. 2007 Oct;8(10):1315-25
references.pmid: 17979506
references.citation: Biochem J. 2009 Jan 1;417(1):43-54
references.pmid: 18778245
references.citation: Biochem Biophys Res Commun. 2006 Mar 10;341(2):451-8
references.pmid: 16426568
references.citation: Nat Rev Cancer. 2005 Mar;5(3):199-209
references.pmid: 15738983
references.citation: Mol Cancer Ther. 2011 Oct;10(10):1982-92
references.pmid: 21831963
references.citation: Anticancer Res. 2003 May-Jun;23(3A):2179-83
references.pmid: 12894594
references.citation: Invest New Drugs. 2012 Aug;30(4):1715-24
references.pmid: 21445578
references.citation: Toxicol Appl Pharmacol. 2009 May 15;237(1):102-10
references.pmid: 19265716
references.citation: J Biol Chem. 2002 May 10;277(19):17009-15
references.pmid: 11884402
references.citation: Tumour Biol. 2014 Aug;35(8):7669-73
references.pmid: 24801906
references.citation: Anticancer Res. 2012 Sep;32(9):3869-74
references.pmid: 22993331
references.citation: Biochim Biophys Acta. 2013 Apr;1831(4):759-68
references.pmid: 23333652
references.citation: J Lipid Res. 2012 Aug;53(8):1610-7
references.pmid: 22591743
references.citation: Acta Oncol. 2014 Jul;53(7):885-91
references.pmid: 24625228
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Semin Cancer Biol. 1999 Apr;9(2):67-81
references.pmid: 10202129
references.citation: Drug Metab Dispos. 2010 Jun;38(6):995-1002
references.pmid: 20233841
references.citation: Nat Genet. 2006 Dec;38(12):1378-85
references.pmid: 17072317
references.citation: Genome Res. 2012 Feb;22(2):246-58
references.pmid: 22156296
references.citation: J Lipid Res. 2008 May;49(5):985-94
references.pmid: 18263853
references.citation: Mol Pharmacol. 2006 Jun;69(6):2007-14
references.pmid: 16551781