Interferon-gamma sensitizes hepatitis B virus-expressing hepatocarcinoma cells to 5-fluorouracil through inhibition of hepatitis B virus-mediated nuclear factor-kappaB activation.
Nuclear factor (NF)-kappaB is important for immune responses and cell survival; however, abnormal activation of NF-kappaB is linked with many types of diseases, including hepatocellular carcinoma (HCC). Our previous report indicated that hepatitis B virus (HBV) induces NF-kappaB activation through NF-kappaB-inducing kinase (NIK), and this can be blocked specifically by interferon (IFN)-gamma. In the present study, we report that HBV expression in HCC cell lines induces drug resistance against 5-fluorouracil (5-FU). This drug resistance was abolished by inhibition of NF-kappaB activation through small interfering RNA-mediated NIK 'knockdown' and IFN-gamma treatment. In addition to the reduced NF-kappaB activation and drug resistance, the upregulated growth arrest- and DNA damage-inducible protein 45beta (Gadd45beta) in HBV-expressing HCC cell lines was downregulated by the small interfering RNA-mediated NIK knockdown and IFN-gamma treatment. The overexpression of Gadd45beta in HCC cell lines also induces drug resistance against 5-FU. Based on our data, we suggest that IFN-gamma treatment might be helpful for chemotherapy in HBV-integrated HCC through inhibition of the NIK-mediated NF-kappaB activation and downregulation of the NF-kappaB target gene Gadd45beta.
Chung
Chan
C
School of Biological Sciences, Seoul National University, Shillim-dong, Kwanak-gu, Seoul 151-742, Korea.
Park
Sung Gyoo
SG
Park
Young Min
YM
Joh
Jae-Won
JW
Jung
Guhung
G
D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000821:virology*; D045744:Cell Line, Tumor; D005472:Fluorouracil / Q000627:therapeutic use*; D017930:Genes, Reporter; D006515:Hepatitis B virus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000821:virology*; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D015183:Restriction Mapping; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D016328:NF-kappa B; D034741:RNA, Small Interfering; D016899:Interferon-beta; D008156:Luciferases; D005472:Fluorouracil
Blood. 2003 Nov 1;102(9):3270-9
12855571
Science. 1965 Jul 16;149(3681):310-1
17533668
J Biol Chem. 2002 Mar 8;277(10):7920-8
11773061
Oncogene. 1991 Jan;6(1):165-7
1899477
Semin Cancer Biol. 2003 Apr;13(2):107-14
12654254
Trends Cell Biol. 2001 Nov;11(11):S22-6
11684438
Proc Natl Acad Sci U S A. 1987 Feb;84(4):1005-9
3029758
BMJ. 1999 May 1;318(7192):1213
10221961
Cancer. 1988 May 15;61(10):1942-56
2834034
Cancer Lett. 2005 Nov 18;229(2):271-81
16135400
Oncogene. 1996 Jun 20;12(12):2579-94
8700517
Cell. 2004 Aug 6;118(3):285-96
15294155
J Biol Chem. 2004 May 28;279(22):23477-85
15026414
Clin Cancer Res. 2001 Oct;7(10):3269-75
11595724
Science. 1994 Nov 25;266(5189):1376-80
7973727
World J Gastroenterol. 2006 Aug 21;12(31):4986-95
16937494
Oncogene. 1995 Nov 2;11(9):1675-83
7478594
Arch Biochem Biophys. 2000 Aug 1;380(1):108-16
10900139
Cell. 1998 Nov 13;95(4):521-30
9827804
Trends Immunol. 2004 Jun;25(6):280-8
15145317
Cancer Treat Rev. 1988 Mar;15(1):1-31
2834053
Cancer Res. 2006 Aug 1;66(15):7598-605
16885359
J Cell Physiol. 1999 Nov;181(2):188-202
10497299
Cancer Res. 2000 Oct 1;60(19):5451-5
11034087
FASEB J. 2001 Nov;15(13):2551-3
11641261
Oncogene. 2002 Sep 19;21(42):6510-9
12226754
Nat Rev Cancer. 2005 Apr;5(4):297-309
15803156
Oncogene. 2006 Aug 7;25(34):4798-811
16892092
Oncogene. 1999 May 6;18(18):2892-900
10362260
J Biol Chem. 2000 Jun 2;275(22):16602-8
10747892
Int J Clin Pharmacol Ther. 2002 Aug;40(8):336-47
12467302
J Biol Chem. 2003 Oct 10;278(41):39851-7
12869561
Gastroenterology. 2005 Jun;128(7):2042-53
15940636
J Virol. 2005 Jul;79(14):8948-59
15994789
J Biol Chem. 2006 Jan 27;281(4):2162-9
16280329
Eur J Cancer. 2004 Jul;40(10):1474-84
15196530
Nat Med. 1999 Apr;5(4):412-7
10202930
J Natl Cancer Inst. 1992 Feb 19;84(4):262-4
1346405
Lancet. 1978 May 13;1(8072):1006-9
76932
Oncogene. 2003 Dec 8;22(56):8961-82
14663476
Oncogene. 2006 Sep 7;25(40):5537-46
16732331
Nature. 2001 Nov 15;414(6861):308-13
11713530
J Biol Chem. 2002 Mar 29;277(13):10842-51
11801607
J Virol. 2007 Jan;81(1):272-9
17035315
EMBO J. 2003 Jun 2;22(11):2552-60
12773372
Oncogene. 1999 Aug 12;18(32):4554-63
10467400
Semin Cancer Biol. 2000 Jun;10(3):211-31
10936070
Nat Rev Cancer. 2003 May;3(5):330-8
12724731
Cell. 2002 Apr;109 Suppl:S81-96
11983155
J Virol. 2001 Jan;75(1):215-25
11119591
Clin Cancer Res. 1999 Jan;5(1):119-27
9918209
Cancer Cell. 2002 Oct;2(4):335-46
12398897
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3706-11
10097101
Cancer Lett. 2002 Oct 8;184(1):97-104
12104053
Cancer Res. 2003 Jan 1;63(1):107-10
12517785
FEBS Lett. 2006 Feb 6;580(3):822-30
16413545
J Clin Invest. 2001 Jan;107(2):135-42
11160126
Oncogene. 2003 May 22;22(21):3243-51
12761494
Cancer Res. 2004 Nov 15;64(22):8167-76
15548681
Oncogene. 2001 Feb 15;20(7):859-68
11314019
Nature. 2004 Sep 23;431(7007):461-6
15329734
J Biol Chem. 2001 Jul 6;276(27):25073-7
11340079
J Hepatol. 2001 Sep;35(3):421-30
11592607
Cancer. 1988 Aug 1;62(3):479-83
2839280
Oncogene. 2000 Aug 24;19(36):4159-69
10962577
Hepatology. 2002 Dec;36(6):1498-508
12447876
J Gastroenterol Hepatol. 1997 Aug;12(8):569-75
9304508