title: Bcl-xL overexpression inhibits taxol-induced Yama protease activity and apoptosis.
abstract: Intracellularly, the anticancer drug taxol induces tubulin polymerization and mitotic arrest, followed by apoptosis. The DNA repair enzyme poly(ADP-ribose) polymerase (PARP) and lamins are known to be degraded during apoptosis. PARP is a substrate for the Yama protease, which is encoded by the CPP32 beta/ Yama gene, whereas lamins are degraded by the Yama and lamin proteases. In the present studies, we determined the effects of enforced overexpression of the antiapoptosis Bcl-xL protein on taxol-mediated microtubule and cell cycle perturbations, as well as on taxol-induced apoptosis and associated Yama protease activity in human myeloid leukemia HL-60 cells. Our data demonstrate that high Bcl-xL levels do not affect the microtubular bundling or mitotic arrest due to taxol but significantly inhibit the morphological, flow cytometric, and DNA fragmentation features associated with taxol-induced apoptosis. This resulted in a significant improvement in the survival of taxol-treated cells that possess high Bcl-xL levels. In the control HL-60 cells, following taxol treatment, whereas the mRNA of Yama was not induced, taxol-induced apoptosis was associated with Yama activation and PARP as well as lamin B1 degradation. These features were blocked by coculture of these cells with the cysteine protease inhibitor YVAD-cmk as well as in cells with overexpression of Bcl-xL. These results suggest that Bcl-xL antagonizes taxol-induced apoptosis by a mechanism that interferes with the activation of a key protease involved in the execution of apoptosis.
authors.affiliation: Department of Medicine, Winship Cancer Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Ibrado
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.forename: G
authors.initials: G
authors.lastname: Fang
authors.forename: K
authors.initials: K
authors.lastname: Bhalla
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D015152:Blotting, Northern; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D053938:DNA Fragmentation / Q000502:physiology; D006801:Humans; D034921:Lamin Type B; D034882:Lamins; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics; D008870:Microtubules / Q000502:physiology; D008938:Mitosis / Q000502:physiology; D009687:Nuclear Proteins / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: C494772:BAK1 protein, human; C494811:BCL2L1 protein, human; D034921:Lamin Type B; D034882:Lamins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases; D017239:Paclitaxel