Identification of new compounds that trigger apoptosome-independent caspase activation and apoptosis.
Identification of alternative pathways of caspase activation is an important step to develop new antitumor treatments. We report here the result of a screening with a small chemical library, the Developmental Therapeutics Program-National Cancer Institute "challenge set," on cells expressing mutated caspase-9. We have identified two molecules capable of activating an apoptosome-independent apoptotic pathway. These compounds, named F6 and G5, target the ubiquitin-proteasome system by inhibiting the ubiquitin isopeptidases. We have shown that F6 and G5 induce a rather unique apoptotic pathway, which includes a Bcl-2-dependent but apoptosome-independent mitochondrial pathway with up-regulation of the BH3-only protein Noxa, stabilization of the inhibitor of apoptosis antagonist Smac, but also the involvement of the death receptor pathway. Noxa plays an important role in the induction of mitochondrial fragmentation and caspase activation, whereas the death receptor pathway becomes critical in the absence of a functional apoptosome. This study suggests that screening of chemical libraries on cancer cells with defined mutations in apoptotic key elements can lead to the identification of compounds that are useful to characterize alternative pathways of caspase activation.
Aleo
Emanuela
E
Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia and MATI Center of Excellence, Universita' di Udine, Udine, Italy.
Henderson
Clare J
CJ
Fontanini
Alessandra
A
Solazzo
Barbara
B
Brancolini
Claudio
C
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D053453:Caspase 9 / Q000235:genetics; D020169:Caspases / Q000378:metabolism*; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D019938:Cyclin D1 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D009578:Nitrobenzenes / Q000494:pharmacology*; D010881:Piperidones / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D025801:Ubiquitin / Q000037:antagonists & inhibitors / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D003499:Cyclic S-Oxides; C412403:DIABLO protein, human; D020536:Enzyme Activators; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; C514996:NSC 144303; C514997:NSC 632839; D009578:Nitrobenzenes; C498702:PMAIP1 protein, human; D010881:Piperidones; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D025801:Ubiquitin; D019938:Cyclin D1; D053453:Caspase 9; D020169:Caspases; D046988:Proteasome Endopeptidase Complex