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Arsenic trioxide-induced neuroblastoma cell death is accompanied by proteolytic activation of nuclear Bax

J Karlsson1, A Pietras, S Beckman

  • 1Department of Laboratory Medicine, Division of Molecular Medicine, University Hospital MAS, Lund University, Malmö, Sweden.

Oncogene
|April 4, 2007
PubMed

Insights

Arsenic trioxide induces cell death in neuroblastoma by cleaving Bax protein into a p18 form, which is trapped in the nucleus, not through classical apoptosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Mechanisms

Background:

  • Arsenic trioxide (As(2)O(3)) exhibits toxicity against multidrug-resistant neuroblastoma cells.
  • The cell death induced by As(2)O(3) in neuroblastoma does not follow the canonical apoptotic pathway.

Purpose of the Study:

  • To elucidate the specific cell death mechanism triggered by As(2)O(3) in neuroblastoma.
  • To investigate the role of Bax cleavage and its cellular localization in As(2)O(3)-induced cell death.

Main Methods:

  • Subcellular fractionation to determine the localization of Bax protein fragments.
  • Analysis of Bax protein levels (p21 and p18 forms) in different cellular compartments.
  • Investigation of the role of calpain protease in Bax cleavage and localization.

Main Results:

  • As(2)O(3) treatment leads to the proteolytic cleavage of Bax into a p18 form.
  • The p18 Bax fragment is predominantly found in nuclear fractions, not mitochondria.
  • Cytoplasmic p21 Bax decreases while total nuclear Bax increases; nuclear calpain activity is induced by As(2)O(3).

Conclusions:

  • As(2)O(3) induces a non-apoptotic cell death pathway in neuroblastoma involving nuclear trapping of cleaved p18 Bax.
  • Calpain-mediated cleavage of Bax within the nucleus is a key event in this As(2)O(3)-induced death mechanism.

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