Maspin mediates increased tumor cell apoptosis upon induction of the mitochondrial permeability transition.
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 maspinDeltaN 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, maspinDeltaRSL. 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.
Latha
Khatri
K
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Zhang
Weiguo
W
Cella
Nathalie
N
Shi
Heidi Y
HY
Zhang
Ming
M
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D045304:Cytochromes c / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006801:Humans; D047468:Immunoprecipitation; D007473:Ion Channels / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000737:chemistry / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D017384:Sequence Deletion / Q000235:genetics; D015843:Serpins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D011506:Proteins; C085344:SERPIN-B5; D015843:Serpins; D025521:Tumor Suppressor Proteins; D045304:Cytochromes c; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases