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Calcium Is A Key Signaling Molecule In β-Lapachone-mediated Cell Death*

C. Tagliarino, J. Pink, G. Dubyak, A. Nieminen, D. Boothman
Published 2001 · Biology

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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 Ca2+ 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.
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