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Cooperation between STAT3 and c-jun suppresses Fas transcription

V N Ivanov1, A Bhoumik, M Krasilnikov

  • 1The Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029, USA.

Molecular Cell
|July 21, 2001
PubMed

Insights

Melanoma progression often decreases Fas expression, hindering Fas-ligand (FasL)-induced apoptosis. Suppressing Stat3 or c-Jun increases Fas expression, restoring apoptosis and potentially improving cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Decreased Fas receptor expression in tumors limits Fas-ligand (FasL)-induced apoptosis, promoting tumor progression and metastasis.
  • Melanoma exhibits an inverse relationship between Fas cell surface expression and its tumorigenicity and metastatic potential.

Purpose of the Study:

  • To investigate the role of Signal Transducer and Activator of Transcription 3 (Stat3) and c-Jun in regulating Fas expression in melanoma.
  • To determine if Stat3 and c-Jun influence melanoma cell sensitivity to FasL-mediated apoptosis.

Main Methods:

  • Utilized dominant-negative Stat3 or c-Jun expression in human and mouse melanoma cells.
  • Assessed Fas cell surface expression and sensitivity to FasL-induced apoptosis in genetically modified melanoma cells (Stat3+/- and c-Jun-/-).
  • Investigated the mechanism of Fas expression suppression by Stat3 and c-Jun, distinguishing it from Stat3-mediated transcriptional activation.

Main Results:

  • Expression of dominant-negative Stat3 or c-Jun significantly increased Fas expression and sensitized melanoma cells to FasL-induced apoptosis.
  • Stat3+/- and c-Jun-/- melanoma cells showed elevated Fas surface expression and enhanced sensitivity to FasL.
  • Stat3 and c-Jun suppress Fas expression through a mechanism independent of Stat3-mediated transcriptional activation.

Conclusions:

  • Stat3 and c-Jun cooperate to downregulate Fas surface expression in melanoma.
  • This downregulation of Fas by Stat3 and c-Jun contributes to tumor therapy resistance and metastasis.
  • Targeting the Stat3-c-Jun interaction may represent a therapeutic strategy to restore Fas-mediated apoptosis in melanoma.

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