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Evidence for the interplay between JNK and p53-DRAM signalling pathways in the regulation of autophagy

Séverine Lorin1, Gérard Pierron, Kevin M Ryan

  • 1INSERM U756, Faculté de Pharmacie, Université Paris-Sud 11, Châtenay-Malabry, France.

Autophagy
|December 2, 2009
PubMed

Insights

The antitumoral compound 2-methoxyestradiol (2-ME) activates p53 and JNK pathways, enhancing autophagy and apoptosis in Ewing sarcoma. This study reveals p53-JNK interplay in regulating autophagy via DRAM and Bcl-2 modulation.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • p53 and JNK pathways regulate apoptosis and autophagy, crucial processes often dysregulated in cancer.
  • Ewing sarcoma cells exhibit deregulated apoptosis and autophagy, presenting therapeutic targets.

Purpose of the Study:

  • To investigate the interplay between p53 and JNK signaling in autophagy regulation.
  • To elucidate the mechanisms by which 2-methoxyestradiol (2-ME) induces autophagy and apoptosis in Ewing sarcoma.

Main Methods:

  • Utilized Ewing sarcoma cell models treated with 2-methoxyestradiol (2-ME).
  • Analyzed the activation of p53 and JNK pathways.
  • Investigated the modulation of autophagy-related proteins, including Bcl-2 and DRAM.
  • Assessed the impact of DRAM silencing on 2-ME-induced effects.

Main Results:

  • 2-methoxyestradiol (2-ME) activated both p53 and JNK pathways, enhancing autophagy and apoptosis.
  • p53 partially regulated JNK activation.
  • JNK modulated autophagy by promoting Bcl-2 phosphorylation and upregulating DRAM.
  • DRAM silencing abrogated 2-ME-induced autophagy and apoptosis.

Conclusions:

  • Established a link between p53, JNK, and autophagy regulation in cancer cells.
  • Demonstrated that JNK activation modulates autophagy through Bcl-2 and DRAM.
  • Highlighted DRAM as a critical mediator of 2-ME's pro-autophagic and pro-apoptotic effects.

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