Granzyme B-induced apoptosis in cancer cells and its regulation (review).

The granzyme B-induced cell death has been traditionally viewed as a primary mechanism that is used by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to eliminate harmful target cells including allogeneic, virally infected and tumour cells. Granzyme B (GrB) is the most abundant serine protease which is stored in secretory granules of CTLs and NK cells. After recognition of the target cell, the engaged CTLs and NK cells vectorially secrete GrB along with other granule proteins including perforin into the immunological synapse. From this submicroscopic intercellular cleft GrB translocates into the cytoplasm of the target cell. Although several models have been proposed to explain the GrB delivery mechanism, conclusive understanding of this process remains still elusive. Once in the cytoplasm, GrB cleaves and activates, or inactivates, multiple protein substrates, resulting eventually into apoptotic demise of the target cell. This review is focused on the gene structure and expression of GrB, its biosynthesis and activation, delivery mechanisms into the target cell cytoplasm, direct proteolytic involvement in activation of several pro-apoptotic pathways, and on regulation of its activity in cancer cells. Moreover, emphasis is given to the GrB-mediated anticancer effects and future clinical applications of the GrB-based and tumour-targeted recombinant fusion constructs.