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- Title
Caspase-dependent cleavage of 170-kDa P-glycoprotein during apoptosis of human T-lymphoblastoid CEM cells.
- Authors
Mantovani, Irina; Cappellini, Alessandra; Tazzari, Pier Luigi; Papa, Veronica; Cocco, Lucio; Martelli, Alberto M.
- Abstract
Multidrug resistance (MDR) mediated by the drug efflux protein, 170-kDa P-glycoprotein (P-gp), is one mechanism that tumor cells use to escape cell death induced by chemotherapeutic drugs. Moreover, evidence suggests that cell lines expressing high levels of 170-kDa P-gp are less sensitive to caspase-mediated apoptosis induced by a wide range of death stimuli, including Fas ligand, tumor necrosis factor, and ultraviolet irradiation. However, the fate of 170-kDa P-gp during apoptosis is unknown. In this study, we demonstrate for the first time that 170-kDa P-gp is cleaved during apoptosis of VBL100 human T-lymphoblastoid CEM cells. Apoptotic cell death was induced by LY294002 (a pharmacological inhibitor of the phosphoinositide 3-kinase/Akt survival pathway), H2O2, and Z-LEHD-FMK (a caspase-9 inhibitor which has been recently reported to induce apoptosis in CEM cells). Using an antibody to a common epitope present in both the third and the sixth extracellular loop of P-gp, two cleavage products were detected, with an apparent molecular weight of 80 and 85 kDa. DEVD-FMK (a caspase-3 inhibitor), but not VEID-CHO (a caspase-6 inhibitor), blocked 170-kDa P-gp cleavage. Recombinant caspase-3 was able to cleave in vitro 170-kDa P-gp yielding two fragments of equal size to those generated in vivo. Considering the size of the cleaved fragments and their reactivity with antibodies, which recognize either the N-half or the C-half region of the protein, it is conceivable that the cleavage occurs intracytoplasmically. Since 170-kDa P-gp has been reported to counteract apoptosis, its cleavage may be a mechanism aimed at blocking an important cell survival component. J. Cell. Physiol. © 2006 Wiley-Liss, Inc.
- Subjects
MULTIDRUG resistance; PROTEINS; TUMORS; CANCER cells; CELL death; THERAPEUTICS; TUMOR necrosis factors
- Publication
Journal of Cellular Physiology, 2006, Vol 207, Issue 3, p836
- ISSN
0021-9541
- Publication type
Article
- DOI
10.1002/jcp.20628