Interferon-resistant Daudi cell line with a Stat2 defect is resistant to apoptosis induced by chemotherapeutic agents.
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.
Du
Ziyun
Z
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
Fan
Meiyun
M
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
Kim
Jong-Gwan
JG
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
Eckerle
Dara
D
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
Lothstein
Leonard
L
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
Wei
Lai
L
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center and Center for Cancer Research, Memphis, Tennessee 38163.
Pfeffer
Lawrence M
LM
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.
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
D000970:Antineoplastic Agents; D016898:Interferon-alpha; D020033:Protein Isoforms; D050795:STAT2 Transcription Factor
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