Potent antitumor agent proteasome inhibitors: a novel trigger for Bcl2 phosphorylation to induce apoptosis.
The sustained cytotoxicity conferred by proteasome inhibitors against a broad spectrum of human cancer cells is mediated by a delicate mechanism of programmed cell death. Similar to microtubule disarraying agents, the cell death induced by these potent antitumor agents precedes blocking in cell cycle transition at G2-M phase. The microtubule damaging antineoplastic drugs can kill tumor cells by inducing phosphorylation of antiapoptotic proteins such as Bcl2, Bcl-xL or MCL-1. The simultaneous apoptosis with Bcl2 phosphorylation was evident in cancer cells challenged with the proteasome inhibitor, MG132. Our studies suggest that the proteasome inhibitor MG132 induced tumor cell killing is mediated through Bcl2 phosphorylation.
You
S A
SA
Rammelkamp Center for Education and Research, Department of Pharmacology, Ireland Cancer Center, MetroHealth/Case Western Reserve University, Cleveland, OH 44109-1998, USA.
Basu
A
A
Haldar
S
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D019169:Jurkat Cells; D007976:Leupeptins / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009097:Multienzyme Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D011065:Poly(ADP-ribose) Polymerases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde