Abstract:
:The novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) induces apoptosis of cancer cells, enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and exhibits potent anticancer activity in animal models with a favorable pharmacokinetic profile. Thus, CDDO-Me is being tested in Phase I clinical trials. In an effort to understand the mechanism by which CDDO-Me induces apoptosis, particularly in human lung cancer cells, we previously demonstrated that CDDO-Me induces apoptosis involving c-Jun N-terminal kinase (JNK)-dependent upregulation of death receptor 5 (DR5) expression. In the current work, we determined the modulatory effects of CDDO-Me on the levels of c-FLIP, a major inhibitor of death receptor-mediated caspase-8 activation, and its impact on CDDO-Me-induced apoptosis and enhancement of TRAIL-induced apoptosis in human lung cancer cells. CDDO-Me rapidly and potently decreased c-FLIP levels including both long (FLIP(L)) and short (FLIP(S)) forms of c-FLIP in multiple human lung cancer cell lines. The presence of the proteasome inhibitor MG132, but not the JNK inhibitor SP600125, prevented CDDO-Me-induced c-FLIP reduction. Moreover, CDDO-Me increased ubiquitination of c-FLIP. Thus, CDDO-Me induces ubiquitin/proteasome-dependent c-FLIP degradation independently of JNK activation. Importantly, overexpression of c-FLIP (e.g., FLIP(L)) protected cells not only from CDDO-Me-induced apoptosis, but also from induction of apoptosis by the combination of CDDO-Me and TRAIL. Accordingly, silencing of c-FLIP with c-FLIP siRNA sensitized cancer cells to CDDO-Me. Collectively, these results indicate that c-FLIP downregulation contributes to CDDO-Me-initiated apoptosis and also to enhancement of TRAIL-induced apoptosis by CDDO-Me.
journal_name
Cancer Biol Therjournal_title
Cancer biology & therapyauthors
Zou W,Chen S,Liu X,Yue P,Sporn MB,Khuri FR,Sun SYdoi
10.4161/cbt.6.10.4763subject
Has Abstractpub_date
2007-10-01 00:00:00pages
1614-20issue
10eissn
1538-4047issn
1555-8576pii
4763journal_volume
6pub_type
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