The marine product cephalostatin 1 activates an ER stress-specific and apoptosome-independent apoptotic signaling pathway

Lopez-Anton N, Rudy A, Barth N, Schmitz ML, Pettit GR, Schulze-Osthoff K, Dirsch VM, Vollmar AM
Source: J Biol Chem
Publication Date: (2006)
Issue: 281(44): 33078-86
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Species: human
Tissue Origin: blood
Species: human
Tissue Origin:
Nucleofectorâ„¢ I/II/2b
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.