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Research Paper
m-Calpain Activation in b-Lapachone-Mediated Apoptosis
Colleen Tagliarino, John J. Pink, Kathryn Reinicke, Sara M. Simmers and David A. Boothman
volume 2 | issue 2
march/april 2003Pages: 141-152
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b-Lapachone (b-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 b-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 b-lap-induced apoptosis. We now show that exposure of NQO1-expressing breast cancer cells to b-lap stimulates a unique proteolytic apoptotic pathway involving m-calpain activation. No apparent activation of m-calpain was noted. Upon activation, m-calpain translocated to the nucleus concomitant with specific nuclear proteolytic events. Apoptotic responses in b-lap-exposed NQO1-expressing cells were significantly delayed and survival enhanced by exogenous over-expression of calpastatin, a natural inhibitor of m- and m-calpains. Furthermore, purified m-calpain cleaved PARP to a unique fragment (~60 kDa), not previously reported for calpains. We provide evidence that b-lap-induced, m-calpain-stimulated apoptosis does not involve any known apoptotic caspases; the activated fragments of caspases were not observed after b-lap exposures, nor were there any changes in the pro-enzyme forms as measured by Western blot analyses. The ability of b-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.
Keywords: b-Lapachone, apoptosis, Ca2+, calpain, breast cancer
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.