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Molecular and Cellular Biology, May 2002, p. 3003-3013, Vol. 22, No. 9
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.9.3003-3013.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Calpain-Mediated Bid Cleavage and Calpain-Independent Bak Modulation: Two Separate Pathways in Cisplatin-Induced Apoptosis

Aleksandra Mandic, Kristina Viktorsson, Linda Strandberg, Thomas Heiden,,{dagger} Johan Hansson, Stig Linder, and Maria C. Shoshan*

Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institute and Hospital, S-171 76 Stockholm, Sweden

Received 24 September 2001/ Returned for modification 30 October 2001/ Accepted 23 January 2002

Calpain is a ubiquitous protease with potential involvement in apoptosis. We report that in human melanoma cells, cisplatin-induced calpain activation occurs early in apoptosis. Calpain activation and subsequent apoptosis were inhibited by calpeptin and PD150606, two calpain inhibitors with different modes of action. Furthermore, cisplatin induced cleavage of the BH3-only protein Bid, yielding a 14-kDa fragment similar to proapoptotic, caspase-cleaved Bid. However, Bid cleavage was inhibited by inhibitors of calpain, but not by inhibitors of caspases or of cathepsin L. Recombinant Bid was cleaved in vitro by both recombinant calpain and by lysates of cisplatin-treated cells. Cleavage was calpeptin sensitive, and the cleavage site was mapped between Gly70 and Arg71. Calpain-cleaved Bid induced cytochrome c release from isolated mitochondria. While calpeptin did not affect cisplatin-induced modulation of Bak to its proapoptotic conformation, a dominant-negative mutant of MEKK1 (dnMEKK) inhibited Bak modulation. dnMEKK did not, however, block Bid cleavage. The combination of dnMEKK and calpeptin had an additive inhibitory effect on apoptosis. In summary, calpain-mediated Bid cleavage is important in drug-induced apoptosis, and cisplatin induces at least two separate apoptotic signaling pathways resulting in Bid cleavage and Bak modulation, respectively.

* Corresponding author. Mailing address: Cancer Center Karolinska R8:03, Department of Oncology-Pathology, Karolinska Institute and Hospital, S-171 76 Stockholm, Sweden. Phone: 46 8 51 77 54 60. Fax: 46 8 33 90 31. E-mail: mimmi.shoshan{at}onkpat.ki.se.

{dagger} Present address: Institute of Medical Genetics, Charite Humboldt University of Berlin, Berlin, Germany.

Molecular and Cellular Biology, May 2002, p. 3003-3013, Vol. 22, No. 9
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.9.3003-3013.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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