The marine product cephalostatin 1 activates an endoplasmic reticulum stress-specific and apoptosome-independent apoptotic signaling pathway.
Cephalostatin 1, a bis-steroidal marine natural product, has been reported to induce apoptosis without the requirement of an active caspase-8 or mitochondrial cytochrome c release and apoptosome formation. Here we show that despite the absence of these events, caspase-9 activation is essential for cephalostatin 1-induced apoptosis. Cephalostatin 1 initiates a rapid endoplasmic reticulum stress response characterized by phosphorylation of eukaryotic initiation factor-2 alpha-subunit and increased expression of the chaperone immunoglobulin heavy chain-binding protein GRP78 as well as the transcription factor C/EBP homologous protein (CHOP)/GADD153. Cephalostatin 1 activates apoptosis signal-regulating kinase 1 and c-Jun N-terminal kinase (JNK). However, this pathway does not play a major role in cephalostatin 1-induced apoptosis, as assessed by stable expression of a dominant negative apoptosis signal-regulating kinase 1. Importantly, the endoplasmic reticulum-associated caspase-4 is required and as shown by biochemical and genetic inhibition experiments, acts upstream of caspase-9 in cephalostatin-induced apoptosis.
López-Antón
Nancy
N
Department of Pharmacy, Center of Drug Research, University of Munich, 81377 Munich, Germany.
Rudy
Anita
A
Barth
Nicole
N
Schmitz
M Lienhard
ML
Schmitz
Lienhard M
LM
Pettit
George R
GR
Schulze-Osthoff
Klaus
K
Dirsch
Verena M
VM
Vollmar
Angelika M
AM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053478:Apoptosomes / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007448:Invertebrates; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019169:Jurkat Cells; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D009792:Oceans and Seas; D010619:Phenazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D013256:Steroids / Q000494:pharmacology*
D053478:Apoptosomes; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D010619:Phenazines; D013141:Spiro Compounds; D013256:Steroids; C454806:cephalostatin I; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D020169:Caspases