title: Interferon-α enhances 5'-deoxy-5-fluorouridine-induced apoptosis by ERK-dependant upregulation of thymidine phosphorylase.
abstract: 5-Florouracil (5-FU) is the basic agent used in the treatment of gastric cancer. Capecitabine, a prodrug of 5-FU, displays increased antitumor efficacy compared with 5-FU in the clinic. 5'-Deoxy-5-fluorouracil (5'-DFUR), the metabolite of capecitabine, is converted to 5-FU by the enzyme thymidine phosphorylase (TP), which is present at high concentrations in human tumors. In this study, we investigated the effect of interferon-α (IFN-α) on the sensitivity of gastric cancer cells to treatment with 5'-DFUR and its relationship with TP expression. Preincubation of gastric cancer cells with IFN-α enhanced 5'-DFUR-induced apoptosis via IFN-α-mediated upregulation of TP. The depletion of TP with small interfering RNA (siRNA) obviously inhibited IFN-α-induced upregulation of TP expression and thus prevented apoptosis induced by IFN-α and 5'-DFUR. Treatment with IFN-α and combined IFN-α and 5'-DFUR treatment were also associated with concomitant activation of ERK signaling. Treatment with the ERK inhibitor PD98059 or depletion of ERK with siRNA partially reversed IFN-α-induced upregulation of TP expression, thus partially preventing apoptosis induced by IFN-α and 5'-DFUR. Taken together, our study shows that IFN-α enhanced 5'-DFUR-induced apoptosis in gastric cancer cells by upregulation of TP expression, which is partially regulated by activation of ERK signaling.
authors.affiliation: Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Yike
authors.initials: Y
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Xu
authors.forename: Yibo
authors.initials: Y
authors.lastname: Fan
authors.forename: Ce
authors.initials: C
authors.lastname: Li
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Huachuan
authors.initials: H
authors.lastname: Zheng
authors.forename: Kezuo
authors.initials: K
authors.lastname: Hou
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Qu
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Liu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D000069287:Capecitabine; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism; D004357:Drug Synergism; D005472:Fluorouracil / Q000031:analogs & derivatives / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009963:Orotic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D034741:RNA, Small Interfering; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C578855:5'-deoxy-5-fluoroorotidine; D016898:Interferon-alpha; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D009963:Orotic Acid; D000069287:Capecitabine; D013939:Thymidine Phosphorylase; D005472:Fluorouracil
references.citation: J Pharmacol Exp Ther. 2011 Jul;338(1):184-94
references.pmid: 21444628
references.citation: J Biol Chem. 2005 Dec 30;280(52):42707-14
references.pmid: 16260419
references.citation: Anticancer Res. 2002 Sep-Oct;22(5):2607-12
references.pmid: 12529971
references.citation: J Toxicol Sci. 2011 Aug;36(4):411-22
references.pmid: 21804305
references.citation: Blood. 2011 Sep 22;118(12):3228-35
references.pmid: 21685374
references.citation: J Clin Oncol. 2006 May 10;24(14):2137-50
references.pmid: 16682732
references.citation: Br J Cancer. 2010 Nov 23;103(11):1680-91
references.pmid: 21045833
references.citation: J Clin Oncol. 2011 Dec 10;29(35):4696-701
references.pmid: 22042945
references.citation: Mol Cell Biochem. 2010 Jul;340(1-2):107-14
references.pmid: 20177738
references.citation: Lancet Oncol. 2011 Jul;12(7):673-80
references.pmid: 21664867
references.citation: J Leukoc Biol. 2008 Apr;83(4):1060-7
references.pmid: 18182457
references.citation: Laryngoscope. 2009 Jan;119(1):82-8
references.pmid: 19117293
references.citation: Ann Surg Oncol. 2008 Apr;15(4):956-60
references.pmid: 18214617
references.citation: Cancer Lett. 2006 Dec 8;244(2):239-46
references.pmid: 16457948
references.citation: Ann Surg. 2005 Aug;242(2):178-87
references.pmid: 16041207
references.citation: Breast Cancer Res Treat. 2012 May;133(1):217-26
references.pmid: 21915635
references.citation: Clin Cancer Res. 1997 Jun;3(6):923-9
references.pmid: 9815767
references.citation: Liver Int. 2006 Oct;26(8):964-75
references.pmid: 16953837
references.citation: Lancet Oncol. 2011 Feb;12(2):144-52
references.pmid: 21256809
references.citation: J Cancer Res Clin Oncol. 2004 Sep;130(9):546-50
references.pmid: 15071737
references.citation: Clin Cancer Res. 2008 Jun 15;14(12):3807-13
references.pmid: 18559600
references.citation: Oncogene. 2009 Apr 30;28(17):1904-15
references.pmid: 19330019
references.citation: Mol Biol Cell. 2008 Jan;19(1):41-50
references.pmid: 17942603
references.citation: Ann Oncol. 2009 Sep;20(9):1529-1534
references.pmid: 19474114
references.citation: Urol Int. 2004;73(4):348-53
references.pmid: 15604581