Initiation of apoptosis and autophagy by the Bcl-2 antagonist HA14-1.
L1210 murine leukemia cells exposed to an LD(90) concentration of the Bcl-2/Bcl-x(L) antagonist HA14-1 rapidly undergo apoptosis but also develop numerous intracellular vacuoles with double membranes, exhibit enhanced labeling by monodansylcadaverine, and convert the cytosolic protein LC3-I to LC3-II. These are hallmarks of autophagy. Autophagic vacuoles develop rapidly, preceding the appearance of an apoptotic nuclear morphology and can be observed in both non-apoptotic and apoptotic cells. Inhibition of autophagy by the PI 3-kinase inhibitor wortmannin promoted apoptosis; conversely inhibition of caspase-3/7 with zDEVD-fmk promoted autophagy. Neither process was dependent on calcium translocation. These results indicate that pharmacological suppression of Bcl-2 function can mimic the induction of autophagy that can occur following the down-regulation of Bcl-2 expression by molecular approaches.
Kessel
David
D
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA. dhkessel@med.wayne.edu
Reiners
John J
JJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D001578:Benzopyrans / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008854:Microscopy, Electron; D009570:Nitriles / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*
D001578:Benzopyrans; D002614:Chelating Agents; D009570:Nitriles; D019253:Proto-Oncogene Proteins c-bcl-2; C456800:ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid