title: γ-Glutamyl hydrolase modulation and folate influence chemosensitivity of cancer cells to 5-fluorouracil and methotrexate.
abstract: BACKGROUND
  γ-Glutamyl hydrolase (GGH) regulates intracellular folate and antifolates for optimal nucleotide biosynthesis and antifolate-induced cytotoxicity, respectively. The modulation of GGH may therefore affect chemosensitivity of cancer cells, and exogenous folate levels may further modify this effect.
  
  
  METHODS
  We generated a novel model of GGH modulation in human HCT116 and MDA-MB-435 cancer cells and investigated the effect of GGH modulation on chemosensitivity to 5-fluorouracil (5FU) and methotrexate (MTX) at different folate concentrations in vitro and in vivo.
  
  
  RESULTS
  Overexpression of GGH significantly decreased chemosensitivity of MDA-MB-435 cells to 5FU and MTX at all folate concentrations as expected. In contrast, in HCT116 cells this predicted effect was observed only at very high folate concentration, and as the folate concentration decreased this effect became null or paradoxically increased. This in vitro observation was confirmed in vivo. Inhibition of GGH significantly increased chemosensitivity of both cancer cells to 5FU at all folate concentrations. Unexpectedly, GGH inhibition significantly decreased chemosensitivity of both cancer cells to MTX at all folate concentrations. In both GGH modulation systems and cell lines, the magnitude of chemosensitivity effect incrementally increased as folate concentration increased.
  
  
  CONCLUSIONS
  Modulation of GGH affects chemosensitivity of cancer cells to 5FU and MTX, and exogenous folate levels can further modify the effects.
authors.affiliation: 1] Department of Nutritional Sciences, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [2] Keenan Research Center, Li Ka Shing Knowledge Institute at St. Michael's Hospital, Toronto, Ontario, Canada M5B 1W8.
authors.forename: S-E
authors.initials: SE
authors.lastname: Kim
authors.forename: P D
authors.initials: PD
authors.lastname: Cole
authors.forename: R C
authors.initials: RC
authors.lastname: Cho
authors.forename: A
authors.initials: A
authors.lastname: Ly
authors.forename: L
authors.initials: L
authors.lastname: Ishiguro
authors.forename: K-J
authors.initials: KJ
authors.lastname: Sohn
authors.forename: R
authors.initials: R
authors.lastname: Croxford
authors.forename: B A
authors.initials: BA
authors.lastname: Kamen
authors.forename: Y-I
authors.initials: YI
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology*; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D011623:gamma-Glutamyl Hydrolase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D034741:RNA, Small Interfering; D005492:Folic Acid; D011623:gamma-Glutamyl Hydrolase; D005472:Fluorouracil; D008727:Methotrexate
references.citation: J Nutr. 2012 May;142(5):886-93
references.pmid: 22437563
references.citation: Biochem Pharmacol. 2001 Apr 1;61(7):857-65
references.pmid: 11274972
references.citation: Mol Cancer Ther. 2007 Nov;6(11):2909-20
references.pmid: 18025275
references.citation: J Clin Pharm Ther. 2009 Jun;34(3):355-61
references.pmid: 19827168
references.citation: J Natl Cancer Inst. 1990 Jul 4;82(13):1107-12
references.pmid: 2359136
references.citation: Int J Cancer. 2003 Feb 20;103(5):587-99
references.pmid: 12494465
references.citation: Int J Cancer. 2000 Sep 15;87(6):771-8
references.pmid: 10956384
references.citation: Br J Cancer. 2000 Feb;82(4):913-23
references.pmid: 10732766
references.citation: Gut. 2011 Dec;60(12):1687-94
references.pmid: 21561879
references.citation: J Natl Cancer Inst. 2004 Jan 21;96(2):134-44
references.pmid: 14734703
references.citation: Clin Chim Acta. 2006 Dec;374(1-2):25-32
references.pmid: 16859665
references.citation: Eur J Cancer. 2008 Feb;44(3):400-7
references.pmid: 18068349
references.citation: J Natl Cancer Inst. 1999 Jul 21;91(14):1233-41
references.pmid: 10413425
references.citation: Blood. 1999 Mar 1;93(5):1677-83
references.pmid: 10029597
references.citation: Pharmacogenomics J. 2013 Jun;13(3):227-34
references.pmid: 22450926
references.citation: Pharmacogenetics. 2004 Aug;14(8):557-67
references.pmid: 15284538
references.citation: Cancer Res. 2001 Jun 1;61(11):4599-604
references.pmid: 11389096
references.citation: Am J Clin Nutr. 2010 Aug;92(2):383-9
references.pmid: 20573790
references.citation: N Engl J Med. 2006 Apr 13;354(15):1578-88
references.pmid: 16531614
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10134-8
references.pmid: 8816764
references.citation: Clin Cancer Res. 2007 Jun 15;13(12):3652-9
references.pmid: 17575230
references.citation: Asian Pac J Cancer Prev. 2012;13(7):3461-4
references.pmid: 22994778
references.citation: Biochem Biophys Res Commun. 2008 Jan 25;365(4):801-7
references.pmid: 18035049
references.citation: Clin Cancer Res. 2002 Jul;8(7):2423-9
references.pmid: 12114448
references.citation: Cancer Res. 1991 Feb 1;51(3):789-93
references.pmid: 1988119
references.citation: Eur J Cancer Clin Oncol. 1987 Dec;23(12):1869-81
references.pmid: 3436351
references.citation: JAMA. 2008 Aug 20;300(7):795-804
references.pmid: 18714059
references.citation: Am J Clin Nutr. 2008 Sep;88(3):763-8
references.pmid: 18779294
references.citation: Exp Ther Med. 2011 Nov;2(6):1097-1103
references.pmid: 22977627
references.citation: Eur J Cancer. 1997 May;33(6):950-9
references.pmid: 9291820
references.citation: Pharmacol Ther. 2000 Mar;85(3):207-15
references.pmid: 10739875
references.citation: Semin Oncol. 1997 Oct;24(5 Suppl 18):S18-30-S18-39
references.pmid: 9420019
references.citation: Pharmacogenetics. 2004 Nov;14(11):733-9
references.pmid: 15564880
references.citation: Gut. 2004 Dec;53(12):1825-31
references.pmid: 15542523
references.citation: Nat Rev Cancer. 2003 May;3(5):330-8
references.pmid: 12724731
references.citation: Cancer Res. 1988 Apr 15;48(8):2149-55
references.pmid: 2450647
references.citation: Biochem Pharmacol. 1983 Jan 1;32(1):41-6
references.pmid: 6187348
references.citation: Cancer Chemother Pharmacol. 2002 Nov;50(5):419-28
references.pmid: 12439601
references.citation: J Biol Chem. 1991 Apr 5;266(10):6181-7
references.pmid: 2007575
references.citation: Adv Exp Med Biol. 1993;338:635-8
references.pmid: 7508171
references.citation: Cancer Res. 1995 Feb 1;55(3):566-73
references.pmid: 7834626
references.citation: Cancer Res. 1993 Aug 15;53(16):3677-80
references.pmid: 8339275
references.citation: Gynecol Oncol. 2008 Dec;111(3):509-15
references.pmid: 18851872
references.citation: Pharmacogenomics. 2007 Feb;8(2):141-50
references.pmid: 17286537
references.citation: Mol Pharmacol. 1997 May;51(5):825-32
references.pmid: 9145921
references.citation: Cancer Res. 2000 Jun 15;60(12):3191-9
references.pmid: 10866310
references.citation: Gene. 2013 Jan 10;512(2):247-50
references.pmid: 23107767
references.citation: Br J Cancer. 2005 Sep 19;93(6):639-46
references.pmid: 16136044
references.citation: J Clin Oncol. 1994 Jan;12(1):14-20
references.pmid: 7677801
references.citation: Ann Oncol. 2012 Jul;23(7):1723-9
references.pmid: 22186609
references.citation: Eur J Clin Pharmacol. 2013 Mar;69(3):377-83
references.pmid: 22763757
references.citation: Biochem Pharmacol. 1989 Jan 15;38(2):335-42
references.pmid: 2914018
references.citation: Br J Clin Pharmacol. 2011 Feb;71(2):237-43
references.pmid: 21219404
references.citation: Int J Cancer. 1993 May 28;54(3):450-5
references.pmid: 8509220
references.citation: Mol Pharmacol. 1995 Sep;48(3):505-11
references.pmid: 7565632
references.citation: Biochem Pharmacol. 2002 Jan 15;63(2):105-15
references.pmid: 11841783
references.citation: J Biol Chem. 1997 Mar 14;272(11):6903-8
references.pmid: 9054377
references.citation: Semin Oncol. 1999 Apr;26(2 Suppl 6):24-32
references.pmid: 10598551
references.citation: Eur J Cancer Clin Oncol. 1981 Nov;17(11):1223-8
references.pmid: 7037424
references.citation: J Biol Chem. 2000 Aug 25;275(34):26599-606
references.pmid: 10856298
references.citation: Cancer Res. 1993 May 15;53(10 Suppl):2227-30
references.pmid: 7683570
references.citation: BMC Cancer. 2013 Feb 01;13:47
references.pmid: 23374458