μ-calpain activation in β-lapachone-mediated apoptosis

Colleen Tagliarino, John J. Pink, Kathryn E. Reinicke, Sara M. Simmers, Shelly M. Wuerzberger-Davis, David A. Boothman

Research output: Contribution to journalArticle

60 Scopus citations

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. Recently, our laboratory showed that β-lap-exposed MCF-7 cells exhibited an early increase in intracellular cytosolic Ca2+ from endoplasmic reticulum stores, and that BAPTA-AM (an intracellular Ca2+ chelator) blocked these early increases and partially inhibited all aspects of β-lap-induced apoptosis. We now show that exposure of NQO1-expressing breast cancer cells to β-lap stimulates a unique proteolytic apoptotic pathway involving μ-calpain activation. No apparent activation of m-calpain was noted. Upon activation, μ-calpain translocated to the nucleus concomitant with specific nuclear proteolytic events. Apoptotic responses in β-lap-exposed NQO1-expressing cells were significantly delayed and survival enhanced by exogenous over-expression of calpastatin, a natural inhibitor of μ - and m-calpains. Furthermore, purified μ-calpain cleaved PARP to a unique fragment (∼60 kDa), not previously reported for calpains. We provide evidence that β-lap-induced, μ-calpain-stimulated apoptosis does not involve any known apoptotic caspases; the activated fragments of caspases were not observed after β-lap exposures, nor were there any changes in the pro-enzyme forms as measured by Western blot analyses. The ability of β-lap to trigger an apparently novel, p53-independent, calpain-mediated apoptotic cell death further support the development of this drug for improved breast cancer therapy.

Original languageEnglish (US)
Pages (from-to)141-152
Number of pages12
JournalCancer Biology and Therapy
Volume2
Issue number2
DOIs
StatePublished - Mar 1 2003

Keywords

  • Apoptosis
  • Breast cancer
  • Ca
  • Calpain
  • β-lapachone

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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  • Cite this

    Tagliarino, C., Pink, J. J., Reinicke, K. E., Simmers, S. M., Wuerzberger-Davis, S. M., & Boothman, D. A. (2003). μ-calpain activation in β-lapachone-mediated apoptosis. Cancer Biology and Therapy, 2(2), 141-152. https://doi.org/10.4161/cbt.2.2.237