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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.
- Source :
-
Molecular cancer research : MCR [Mol Cancer Res] 2010 Apr; Vol. 8 (4), pp. 539-53. Date of Electronic Publication: 2010 Apr 06. - Publication Year :
- 2010
-
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 (EC(50)), <3 micromol/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.<br /> ((c) 2010 AACR.)
- Subjects :
- Animals
Cell Death genetics
Cell Line, Tumor
Cell Proliferation
Cell Survival genetics
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic metabolism
Cells, Cultured
Humans
Mice
Molecular Chaperones chemistry
Molecular Chaperones metabolism
Neoplasms genetics
Neoplasms metabolism
Peptides chemical synthesis
Protein Binding genetics
Protein Inhibitors of Activated STAT chemistry
Protein Inhibitors of Activated STAT metabolism
Protein Structure, Tertiary genetics
STAT3 Transcription Factor metabolism
Signal Transduction genetics
Transduction, Genetic methods
Tumor Suppressor Proteins genetics
Tumor Suppressor Proteins metabolism
Genetic Therapy methods
Molecular Chaperones genetics
Neoplasms therapy
Peptides genetics
Protein Inhibitors of Activated STAT genetics
Recombinant Proteins genetics
STAT3 Transcription Factor genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3125
- Volume :
- 8
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cancer research : MCR
- Publication Type :
- Academic Journal
- Accession number :
- 20371673
- Full Text :
- https://doi.org/10.1158/1541-7786.MCR-09-0417