Calcium Is a Key Signaling Molecule in β-Lapachone-mediated Cell Death

Colleen Tagliarino, John J. Pink, George R. Dubyak, Anna Liisa Nieminenll, David A. Boothman

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Abstract

β-Lapachone (β-Lap) triggers apoptosis in a number of human breast and prostate cancer cell lines through a unique apoptotic pathway that is dependent upon NQO1, a two-electron reductase. Downstream signaling pathway(s) that initiate apoptosis following treatment with β-Lap have not been elucidated. Since calpain activation was suspected in β-Lap-mediated apoptosis, we examined alterations in Ca2+ homeostasis using NQO1-expressing MCF-7 cells. β-Lap-exposed MCF-7 cells exhibited an early increase in intracellular cytosolic Ca2+, from endoplasmic reticulum Ca2+ stores, comparable to thapsigargin exposures. 1,2-Bis-(2-aminophenoxy)ethane-N,N,N′N′-tetraacetic acid-acetoxymethyl ester, an intracellular Ca2+ chelator, blocked early increases in Ca2+ levels and inhibited β-Lap-mediated mitochondrial membrane depolarization, intracellular ATP depletion, specific and unique substrate proteolysis, and apoptosis. The extracellular Ca 2+ chelator, EGTA, inhibited later apoptotic end points (observed >8 h, e.g. substrate proteolysis and DNA fragmentation), suggesting that later execution events were triggered by Ca2+ influxes from the extracellular milieu. Collectively, these data suggest a critical, but not sole, role for Ca2+ in the NQO1-dependent cell death pathway initiated by β-Lap. Use of β-Lap to trigger an apparently novel, calpain-like-mediated apoptotic cell death could be useful for breast and prostate cancer therapy.

Original languageEnglish (US)
Pages (from-to)19150-19159
Number of pages10
JournalJournal of Biological Chemistry
Volume276
Issue number22
DOIs
StatePublished - Jun 1 2001

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Tagliarino, C., Pink, J. J., Dubyak, G. R., Nieminenll, A. L., & Boothman, D. A. (2001). Calcium Is a Key Signaling Molecule in β-Lapachone-mediated Cell Death. Journal of Biological Chemistry, 276(22), 19150-19159. https://doi.org/10.1074/jbc.M100730200