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Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen
19:44

Enhancement of Apoptotic and Autophagic Induction by a Novel Synthetic C-1 Analogue of 7-deoxypancratistatin in Human Breast Adenocarcinoma and Neuroblastoma Cells with Tamoxifen

Published on: May 30, 2012

c-Jun activation is required for 4-hydroxytamoxifen-induced cell death in breast cancer cells

A Madeo1, M Vinciguerra, R Lappano

  • 1Department of Pharmaco-Biology, University of Calabria, Rende, Cosenza, Italy.

Oncogene
|November 26, 2009
PubMed

Insights

The c-Jun/c-Fos AP-1 complex promotes apoptosis in cancer cells treated with 4-hydroxytamoxifen (OHT). Activating c-Jun may enhance tamoxifen therapy effectiveness by sensitizing cancer cells to OHT-induced death.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Tamoxifen is a widely used breast cancer treatment.
  • The c-Jun N-terminal kinase (JNK) pathway mediates tamoxifen-induced apoptosis.
  • Downstream mediators of JNK in tamoxifen-induced apoptosis remain unclear.

Purpose of the Study:

  • To investigate the role of c-Jun, a JNK target, in tamoxifen-induced apoptosis.
  • To identify downstream mediators of the JNK pathway in tamoxifen response.
  • To explore the therapeutic potential of targeting the c-Jun pathway.

Main Methods:

  • Utilized SkBr3 breast cancer cells and tamoxifen-sensitive/resistant cell lines.
  • Analyzed JNK-dependent c-Jun phosphorylation and ERK-dependent c-Fos expression.
  • Employed dominant-negative constructs to block AP-1 activity and c-Jun phosphorylation.
  • Assessed DNA fragmentation and caspase 3/7 activation.

Main Results:

  • 4-hydroxytamoxifen (OHT) induced JNK-dependent c-Jun phosphorylation and ERK-dependent c-Fos expression.
  • Blocking AP-1 or c-Jun phosphorylation prevented OHT-induced DNA fragmentation.
  • c-Fos expression and c-Jun phosphorylation preceded caspase activation in sensitive cells.
  • These effects were not observed in OHT-resistant prostate cancer cells.

Conclusions:

  • The c-Jun/c-Fos AP-1 complex plays a pro-apoptotic role in OHT-treated cancer cells.
  • c-Jun activation is a key event in tamoxifen-induced apoptosis.
  • Enhancing c-Jun activation could sensitize cancer cells to tamoxifen therapy, suggesting combination treatment strategies.

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