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Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: a major role of calpain inhibition in cell death protection and p53 status

Oncogene volume 26, pages 2717–2726 (2007)Cite this article

Abstract

The contribution of different proteolytic systems, in particular calpains and effector caspases, in apoptotic cell death is still controversial. In this paper, we show that during cisplatin-induced apoptosis of human metastatic melanoma cells, calpain activation, as measured in intact cells by two different fluorescent substrates, is an early event, taking place well before caspase-3/-7 activation, and progressively increasing during 48 h of treatment. Such activation appears to be independent from any intracellular calcium imbalance; in fact, an increase of cytosolic calcium along with emptying of the reticular stores occur only at very late stages, uniquely in frankly apoptotic, detached cells. Calpain activation proves to be an early and crucial event in the apoptotic machinery, as demonstrated by the significant protection of cell death in samples co-treated with the calpain inhibitors, MDL 28170, calpeptin and PD 150606, where a variable but significant reduction of both caspase-3/-7 activity and cell detachment is observed. Consistently, such a protective effect can be at least partially due to the impairment of cisplatin-induced p53 activation, occurring early in committed, preapoptotic cells. Furthermore, in late apoptotic cells, calpain activity is also responsible for the formation of a novel p53 proteolytic fragment (≈26 kDa), whose function is so far to be elucidated.

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Acknowledgements

We thank Dr R Giunti for technical assistance in calcium measurements. This work was supported by grants from University of Siena (Research Project to EM).

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  1. Department of Physiopathology and Experimental Medicine, University of Siena, Siena, Italy

    B Del Bello, D Moretti, A Gamberucci & E Maellaro

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  1. B Del Bello
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Correspondence to E Maellaro.

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Del Bello, B., Moretti, D., Gamberucci, A. et al. Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: a major role of calpain inhibition in cell death protection and p53 status. Oncogene 26, 2717–2726 (2007). https://doi.org/10.1038/sj.onc.1210079

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