title: Interferon-resistant Daudi cell line with a Stat2 defect is resistant to apoptosis induced by chemotherapeutic agents.
abstract: Interferon-alpha (IFNalpha) has shown promise in the treatment of various cancers. However, the development of IFN resistance is a significant drawback. Using conditions that mimic in vivo selection of IFN-resistant cells, the RST2 IFN-resistant cell line was isolated from the highly IFN-sensitive Daudi human Burkitt lymphoma cell line. The RST2 cell line was resistant to the antiviral, antiproliferative, and gene-induction actions of IFNalpha. Although STAT2 mRNA was present, STAT2 protein expression was deficient in RST2 cells. A variant STAT2 mRNA, which resulted from alternative splicing within the intron between exon 19 and 20, was expressed in several human cell lines but at relatively high levels in RST2 cells. Most importantly, the RST2 line showed an intrinsic resistance to apoptosis induced by a number of chemotherapeutic agents (camptothecin, staurosporine, and doxorubicin). Expression of STAT2 in RST2 cells not only rescued their sensitivity to the biological activities of IFNs but also restored sensitivity to apoptosis induced by these chemotherapeutic agents. The intrinsic resistance of the RST2 cells to IFN as well as chemotherapeutic agents adds a new dimension to our knowledge of the role of STAT2 as it relates to not only biological actions of IFN but also resistance to chemotherapy-induced apoptosis.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
authors.forename: Ziyun
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
authors.forename: Meiyun
authors.initials: M
authors.lastname: Fan
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
authors.forename: Jong-Gwan
authors.initials: JG
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
authors.forename: Dara
authors.initials: D
authors.lastname: Eckerle
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
authors.forename: Leonard
authors.initials: L
authors.lastname: Lothstein
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163. Electronic address: lpfeffer@utmem.edu.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Pfeffer
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D016898:Interferon-alpha; D020033:Protein Isoforms; D050795:STAT2 Transcription Factor
references.citation: J Biol Chem. 1996 May 31;271(22):13221-7
references.pmid: 8675499
references.citation: Oncogene. 1999 Nov 22;18(49):6938-47
references.pmid: 10602468
references.citation: J Cell Biochem. 2007 Dec 1;102(5):1087-94
references.pmid: 17910035
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13631-6
references.pmid: 11095741
references.citation: Science. 1996 Nov 1;274(5288):784-7
references.pmid: 8864119
references.citation: Science. 1994 Jun 3;264(5164):1415-21
references.pmid: 8197455
references.citation: Nat Rev Immunol. 2005 May;5(5):375-86
references.pmid: 15864272
references.citation: Science. 1997 Nov 28;278(5343):1630-2
references.pmid: 9374464
references.citation: Proc Natl Acad Sci U S A. 1998 May 12;95(10):5568-72
references.pmid: 9576923
references.citation: J Biol Chem. 2001 Apr 27;276(17):13756-61
references.pmid: 11278812
references.citation: Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7836-9
references.pmid: 1502203
references.citation: J Biol Chem. 1996 Apr 5;271(14):8057-61
references.pmid: 8626489
references.citation: Cancer Res. 1990 May 1;50(9):2654-7
references.pmid: 2139358
references.citation: Cancer Res. 1991 Nov 1;51(21):5881-7
references.pmid: 1718587
references.citation: Biochemistry. 1999 Mar 23;38(12):3457-61
references.pmid: 10090731
references.citation: J Immunol. 2007 Jan 15;178(2):986-92
references.pmid: 17202361
references.citation: Nucleic Acids Res. 1995 Feb 11;23(3):459-63
references.pmid: 7885841
references.citation: J Clin Virol. 2004 Jun;30(2):115-33
references.pmid: 15125867
references.citation: Nat Med. 1999 Apr;5(4):412-7
references.pmid: 10202930
references.citation: Science. 2009 Feb 6;323(5915):793-7
references.pmid: 19131594
references.citation: Curr Drug Metab. 2007 Jan;8(1):47-57
references.pmid: 17266523
references.citation: Proc Natl Acad Sci U S A. 1994 May 24;91(11):4806-10
references.pmid: 7545930
references.citation: Nat Genet. 1998 Nov;20(3):266-72
references.pmid: 9806545
references.citation: Blood. 1994 Sep 15;84(6):1942-9
references.pmid: 8080997
references.citation: J Biol Chem. 2005 Apr 1;280(13):13029-36
references.pmid: 15668228
references.citation: Am J Physiol. 1999 Feb;276(2):C419-25
references.pmid: 9950769
references.citation: Science. 1997 May 30;276(5317):1418-20
references.pmid: 9162009
references.citation: Cancer Res. 1998 Jun 15;58(12):2489-99
references.pmid: 9635566
references.citation: J Urol. 1996 Nov;156(5):1867-71
references.pmid: 8863634
references.citation: Mol Cell Biol. 1995 Mar;15(3):1312-7
references.pmid: 7532278
references.citation: FEBS Lett. 1996 Mar 4;381(3):191-4
references.pmid: 8601453
references.citation: J Biol Chem. 2004 Sep 17;279(38):39199-206
references.pmid: 15175343
references.citation: J Biol Chem. 2006 Apr 28;281(17):11678-84
references.pmid: 16517601
references.citation: Curr Med Chem Anticancer Agents. 2001 Aug;1(2):113-30
references.pmid: 12678762
references.citation: Biochem J. 2003 Apr 15;371(Pt 2):361-7
references.pmid: 12523936
references.citation: Harvey Lect. 1997-1998;93:1-16
references.pmid: 10941415
references.citation: Cancer Res. 2007 Oct 1;67(19):9214-20
references.pmid: 17909027
references.citation: Immunity. 2000 Dec;13(6):795-804
references.pmid: 11163195
references.citation: Cancer Res. 2005 Feb 1;65(3):939-47
references.pmid: 15705894
references.citation: J Biol Chem. 1997 Nov 7;272(45):28779-85
references.pmid: 9353349