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Defects in death-inducing signalling complex formation prevent JNK activation and Fas-mediated apoptosis in DU 145

J F Curtin1, T G Cotter

  • 1Department of Biochemistry, University College Cork, Lee Maltings, Prospect Row, Cork, Ireland.

British Journal of Cancer
|November 13, 2003
PubMed

Insights

Androgen-independent prostate cancer cells resist apoptosis due to defective death-inducing signaling complex formation. Specifically, FADD fails to interact with caspase-8, preventing JNK activation and cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Androgen-independent prostate carcinomas exhibit resistance to chemotherapy and apoptosis.
  • DU 145 cells, a model for androgen-independent prostate cancer, are resistant to Fas-mediated apoptosis.
  • JNK (c-Jun N-terminal kinase) activation is crucial for Fas-mediated apoptosis in DU 145 cells.

Purpose of the Study:

  • To investigate the mechanisms underlying the abrogation of JNK activation and apoptosis in DU 145 cells.
  • To determine the role of HSP27 and its interaction with DAXX in Fas-mediated apoptosis resistance.
  • To identify the specific defect in the death-inducing signaling complex (DISC) formation.

Main Methods:

  • Incubation of DU 145 cells with anti-Fas IgM agonistic antibody.
  • Analysis of JNK activation.
  • Investigation of protein-protein interactions, including HSP27-DAXX and FADD-caspase-8 interactions.

Main Results:

  • HSP27 is overexpressed in DU 145 cells, but no evidence of HSP27-DAXX interaction was found.
  • Fas receptor activation failed to induce JNK activation and apoptosis.
  • Defective death-inducing signaling complex formation was observed due to the lack of interaction between FADD and caspase-8.

Conclusions:

  • The resistance to Fas-mediated apoptosis in DU 145 cells is not due to HSP27 sequestering DAXX.
  • The primary mechanism for apoptosis resistance involves a defect in DISC formation, specifically the failure of FADD to interact with caspase-8.
  • This FADD-caspase-8 interaction defect prevents downstream signaling, including JNK activation, leading to resistance to apoptosis in androgen-independent prostate cancer cells.

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