Skip NavigationSkip to Content
Return Return to Search Results

Resistance to IFN-alpha-Induced Apoptosis Is Linked to a Loss of STAT2

  1. Author:
    Romero-Weaver, A. L.
    Wang, H. W.
    Steen, H. C.
    Scarzello, A. J.
    Hall, V. L.
    Sheikh, F.
    Donnelly, R. P.
    Gamero, A. M.

  2. Author Address

    [Romero-Weaver, Ana L.; Wang, Hsiang-Wen; Scarzello, Anthony J.; Hall, Veronica L.; Gamero, Ana M.] NCI, Expt Immunol Lab, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. [Steen, Hakan C.; Gamero, Ana M.] Temple Univ, Sch Med, Dept Biochem, Philadelphia, PA 19122 USA. [Sheikh, Faruk; Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA.;Gamero, AM, 3440 N Broad St,Kresge Hall,Room 622, Philadelphia, PA 19041 USA.;gameroa@temple.edu
    1. Year: 2010
    2. Date: Jan
  2. Journal: Molecular Cancer Research
    1. 8
    2. 1
    3. Pages: 80-92
  4. Type of Article: Article
  5. ISSN: 1541-7786
  1. Abstract:

    Type I IFNs (IFN-alpha/beta) are pleitropic cytokines widely used in the treatment of certain malignancies, hepatitis B and C, and multiple sclerosis. IFN resistance is a challenging clinical problem to overcome. Hence, understanding the molecular mechanism by which IFN immunotherapy ceases to be effective is of translational importance. In this study, we report that continuous IFN-alpha stimulation of the human Jurkat variant H123 led to resistance to type I IFN-induced apoptosis due to a loss of signal transducers and activators of transcription 2 (STAT2) expression. The apoptotic effects of IFN-alpha were hampered as STAT2-deficient cells were defective in activating the mitochondrial-dependent death pathway and ISGF3-mediated gene activation. Reconstitution of STAT2 restored the apoptotic effects of IFN-alpha as measured by the loss of mitochondrial membrane potential, cytochrome c release from mitochondria, caspase activation, and ultimately cell death. Nuclear localization of STAT2 was a critical event as retention of tyrosine-phosphorylated STAT2 in the cytosol was not sufficient to activate apoptosis. Furthermore, silencing STAT2 gene expression in Saos2 and A375S.2 tumor cell lines significantly reduced the apoptotic capacity of IFN-alpha. Altogether, we show that STAT2 is a critical mediator in the activation of type I IFN-induced apoptosis. More importantly, defects in the expression or nuclear localization of STAT2 could lessen the efficacy of type I IFN immunotherapy. Mol Cancer Res; 8(1); 80-92. (C) 2010 AACR.

    See More

  1. Keywords:

External Sources

  1. View Full Text
  2. DOI: 10.1158/1541-7786.mcr-08-0344
  3. View record in Web of Science®
  4. WOS: 000278404700008

Library Notes

  1. Fiscal Year: FY2009-2010
NCI at Frederick

You are leaving a government website.

This external link provides additional information that is consistent with the intended purpose of this site. The government cannot attest to the accuracy of a non-federal site.

Linking to a non-federal site does not constitute an endorsement by this institution or any of its employees of the sponsors or the information and products presented on the site. You will be subject to the destination site's privacy policy when you follow the link.

ContinueCancel