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Execution of BMP-4-induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells

N Fukuda1, M Saitoh, N Kobayashi

  • 1Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Oncogene
|February 2, 2006
PubMed

Insights

Bone morphogenic protein (BMP)-4 triggers cancer cell death by activating p53 and causing endoplasmic reticulum (ER) stress. This mechanism is key for treating multiple myeloma, especially in cells with functional p53.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Bone morphogenic protein (BMP)-4 inhibits myeloma cell proliferation and induces apoptosis.
  • The precise molecular mechanisms underlying BMP-4-mediated apoptosis remain largely unelucidated.

Purpose of the Study:

  • To investigate the roles of p53 and the endoplasmic reticulum (ER) in BMP-4-induced apoptosis.
  • To explore the sensitivity of multiple myeloma cells to BMP-4 based on p53 status and ER enrichment.

Main Methods:

  • Treatment of mouse hybridoma HS-72 cells and multiple myeloma cells with BMP-4.
  • Analysis of proapoptotic protein expression (puma, bax).
  • Assessment of p53-dependency, Ca(2+) release from the ER, caspase-12 activation, and ER dysfunction.

Main Results:

  • BMP-4 (3 ng/ml) induced puma and bax expression via a p53-dependent pathway.
  • BMP-4 triggered Ca(2+) release from the ER, leading to caspase-12 activation and ER dysfunction.
  • Multiple myeloma cells with wild-type p53 exhibited significantly higher sensitivity to BMP-4-induced apoptosis.

Conclusions:

  • Wild-type p53 status is crucial for ER dysfunction during BMP-4-induced apoptosis in ER-enriched cells.
  • Sensitivity to BMP-4-induced apoptosis is determined by the presence of wild-type p53 and ER enrichment.
  • ER stress-inducing agents show potential for treating multiple myeloma.

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