Apoptotic Caspases-3 and -7 Cleave Extracellular Domains of Membrane-Bound Proteins from MDA-MB-231 Breast Cancer Cells.

Apoptotic executioner caspases-3 and -7 are the main proteases responsible for the execution of apoptosis. Apoptosis is the main form of programmed cell death involved in organism development and maintenance of homeostasis and is commonly impaired in various pathologies. Predominately an immunologically silent form of cell death, it can become immunogenic upon loss of membrane integrity during progression to secondary necrosis, which mostly occurs when apoptotic bodies are not efficiently cleared by efferocytosis. In cancer, the efferocytic capacity can be overwhelmed following chemotherapeutic treatment, thereby providing an opportunity for the potential extracellular functions of executioner apoptotic caspases in the tumor microenvironment. By triggering apoptosis in Jurkat E6.1 acute T cell leukemia cells, we demonstrated that during progression to secondary necrosis, executioner caspases-3 and -7 can be found in the extracellular space. Furthermore, we showed that extracellularly active caspases-3 and -7 can cleave extracellular domains of membrane-bound proteins from MDA-MB-231 breast cancer cells, a function generally executed in the tumor microenvironment by several extracellular proteases from metalloprotease and cathepsin families. As such, this study provides the evidence for the potential involvement of apoptotic caspases-3 and -7 in extracellular proteolytic networks. Presented mass spectrometry data are available via ProteomeXchange with identifier PXD061399.