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Molecular Cancer Research
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Cell Cycle, Cell Death, and Senescence

The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death

Corina Borghouts, Hanna Tittmann, Natalia Delis, Marisa Kirchenbauer, Boris Brill and Bernd Groner
Corina Borghouts
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Hanna Tittmann
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Natalia Delis
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Marisa Kirchenbauer
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Boris Brill
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Bernd Groner
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DOI: 10.1158/1541-7786.MCR-09-0417 Published April 2010
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Abstract

Signaling components, which confer an “addiction” phenotype on cancer cells, represent promising drug targets. The transcription factor signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many different types of tumor cells and its activity is indispensible in a large fraction. We found that the expression of the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3 (PIAS3), positively correlates with STAT3 activation in normal cells. This suggests that PIAS3 controls the extent and the duration of STAT3 activity in normal cells and thus prevents its oncogenic function. In cancer cells, however, the expression of PIAS3 is posttranscriptionally suppressed, possibly enhancing the oncogenic effects of activated STAT3. We delimited the interacting domains of STAT3 and PIAS3 and identified a short fragment of the COOH-terminal acidic region of PIAS3, which binds strongly to the coiled-coil domain of STAT3. This PIAS3 fragment was used to derive the recombinant STAT3-specific inhibitor rPP-C8. The addition of a protein transduction domain allowed the efficient internalization of rPP-C8 into cancer cells. This resulted in the suppression of STAT3 target gene expression, in the inhibition of migration and proliferation, and in the induction of apoptosis at low concentrations [half maximal effective concentration (EC50), <3 μmol/L]. rPP-C8 did not affect normal fibroblasts and represents an interesting lead for the development of novel cancer drugs targeting the coiled-coil domain of STAT3. Mol Cancer Res; 8(4); 539–53. ©2010 AACR.

Footnotes

    • Received September 15, 2009.
    • Revision received January 28, 2010.
    • Accepted February 16, 2010.
  • ©2010 American Association for Cancer Research.
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Molecular Cancer Research: 8 (4)
April 2010
Volume 8, Issue 4
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The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death
Corina Borghouts, Hanna Tittmann, Natalia Delis, Marisa Kirchenbauer, Boris Brill and Bernd Groner
Mol Cancer Res April 1 2010 (8) (4) 539-553; DOI: 10.1158/1541-7786.MCR-09-0417

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The Intracellular Delivery of a Recombinant Peptide Derived from the Acidic Domain of PIAS3 Inhibits STAT3 Transactivation and Induces Tumor Cell Death
Corina Borghouts, Hanna Tittmann, Natalia Delis, Marisa Kirchenbauer, Boris Brill and Bernd Groner
Mol Cancer Res April 1 2010 (8) (4) 539-553; DOI: 10.1158/1541-7786.MCR-09-0417
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Molecular Cancer Research
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