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Molecular and Cellular Biology, March 2005, p. 1737-1748, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1737-1748.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Maspin Mediates Increased Tumor Cell Apoptosis upon Induction of the Mitochondrial Permeability Transition

Khatri Latha, Weiguo Zhang, Nathalie Cella, Heidi Y. Shi, and Ming Zhang*

Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas

Received 14 April 2004/ Returned for modification 18 June 2004/ Accepted 7 December 2004

Maspin is a unique serpin with the ability to suppress certain types of malignant tumors. It is one of the few p53-targeted genes involved in tumor invasion and metastasis. With this in mind, we attempted to study the molecular mechanism behind this tumor suppression. Maspin-expressing mammary tumors are more susceptible to apoptosis in both implanted mammary tumors in vivo, a three-dimensional spheroid culture system, as well as in monolayer cell culture under lowered growth factors. Subcellular fractionation shows that a fraction of maspin (in both TM40D-Mp and mutant maspin{Delta}N cells) translocates to the mitochondria. This translocation of maspin to the mitochondria is linked to the opening of the permeability transition pore, which in turn causes the loss of transmembrane potential, thus initiating apoptotic degradation. This translocation is absent in the other mutant, maspin{Delta}RSL. It fails to cause any loss of membrane potential and also shows decreased caspase 3 levels, proving that translocation to the mitochondria is a key event for this increase in apoptosis by maspin. Suppression of maspin overexpression by RNA interference desensitizes cells to apoptosis. Our data indicate that maspin inhibits tumor progression through the mitochondrial apoptosis pathway. These findings will be useful for maspin-based therapeutic interventions against breast cancer.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030. Phone: (713) 798-3817. Fax: (713) 798-3817. E-mail: mzhang{at}bcm.tmc.edu.

Molecular and Cellular Biology, March 2005, p. 1737-1748, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1737-1748.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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