Maspin mediates increased tumor cell apoptosis upon induction of the mitochondrial permeability transition

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

*Corresponding author for this work

Research output: Contribution to journalArticle

65 Scopus citations

Abstract

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 maspinΔN cells) translocates to the mitochondria. This transiocation 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, maspinΔRSL. 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.

Original languageEnglish (US)
Pages (from-to)1737-1748
Number of pages12
JournalMolecular and cellular biology
Volume25
Issue number5
DOIs
StatePublished - Mar 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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