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Epidermal growth factor and serum activate distinct pathways to inhibit the BH3 only protein BAD in prostate

O S P Chao1, M-V Clément

  • 1Department of Biochemistry, Faculty of Medicine, National University of Singapore, Singapore.

Oncogene
|June 13, 2006
PubMed

Insights

Understanding prostate cancer cell survival pathways is crucial for targeted therapies. Epidermal growth factor and serum inhibit cell death by affecting BAD and BAX protein translocation, independent of phosphatidylinositol 3-kinase signaling.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Signaling

Background:

  • Understanding prostate cancer cell survival mechanisms is key to developing targeted therapies.
  • Phosphatidylinositol 3-kinase (PI3K) inhibitors like LY294002 induce apoptosis in LNCaP cells, but this is counteracted by serum or epidermal growth factor (EGF).
  • The intracellular pathways mediating this survival signaling remain poorly defined.

Purpose of the Study:

  • To investigate the mechanisms by which serum or EGF inhibit LY294002-induced apoptosis in LNCaP prostate cancer cells.
  • To elucidate the role of BAD and BAX protein translocation and phosphorylation in PI3K-independent survival pathways.

Main Methods:

  • Cell death was quantified by sub-G1 phase analysis and caspase 3 activity assays.
  • Protein phosphorylation and translocation were assessed using Western blotting for BAD, ERK1/2, and RSKs.
  • Gene knockdown of BAD, BAX, RSK1, and RSK2 was performed via siRNA transfection.

Main Results:

  • LY294002-induced cell death involves the mitochondrial translocation of BAD and BAX proteins.
  • EGF activates the MAPK/ERK/RSK1 pathway, leading to BAD phosphorylation at Ser75 and its inactivation.
  • Serum promotes survival by creating an intracellular environment that inhibits the mitochondrial translocation of dephosphorylated BAD.

Conclusions:

  • Phosphorylation of BAD or inhibition of its mitochondrial translocation are critical PI3K-independent survival pathways in LNCaP cells.
  • These findings highlight novel therapeutic targets for overcoming resistance to PI3K-targeted therapies in prostate cancer.

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