PT  - JOURNAL ARTICLE
AU  - Kalli, Kimberly R.
AU  - Devine, Kathryn E.
AU  - Cabot, Myles C.
AU  - Arnt, Christina R.
AU  - Heldebrant, Michael P.
AU  - Svingen, Phyllis A.
AU  - Erlichman, Charles
AU  - Hartmann, Lynn C.
AU  - Conover, Cheryl A.
AU  - Kaufmann, Scott H.
TI  - Heterogeneous Role of Caspase-8 in Fenretinide-Induced Apoptosis in Epithelial Ovarian Carcinoma Cell Lines
AID  - 10.1124/mol.64.6.1434
DP  - 2003 Dec 01
TA  - Molecular Pharmacology
PG  - 1434--1443
VI  - 64
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/64/6/1434.short
4100  - http://molpharm.aspetjournals.org/content/64/6/1434.full
SO  - Mol Pharmacol2003 Dec 01; 64
AB  - The mechanism of action of fenretinide, a synthetic retinoid currently undergoing testing as a chemopreventive and chemotherapeutic agent, is incompletely understood. In the present study, fenretinide caused apoptotic changes, including DNA fragmentation and cleavage of caspase substrates, in six low-passage ovarian cancer cell lines. However, the caspase activation pathway used by this agent varied. Transient transfection of cDNA-encoding cytokine response modifier A (CrmA), a caspase-8 inhibitor, diminished fenretinide-induced death in OV177 cells. Likewise, IETD(OMe)-fluoromethylketone (fmk) inhibited fenretinide-induced apoptosis by >80% in OV177 or OV266 cells and by ∼50% in OV17, OV167, or OV207 cells. Further analysis demonstrated that inhibition of Fas ligand, tumor necrosis factor-α, or TRAIL signaling with blocking reagents did not affect fenretinide-induced apoptosis, raising the possibility that fenretinide activates caspase-8 in a death receptor-independent manner. In contrast, CrmA transfection or IETD(OMe)-fmk treatment did not inhibit fenretinide-induced apoptosis in OV202 cells. These divergent behaviors did not correlate with increased levels of procaspase-10, which is relatively resistant to CrmA and IETD(OMe)-fmk, nor with the expression of procaspase-8 and -9, apoptotic protease activating factor-1, or cellular FLICE-like inhibitory protein. Similarly, fenretinide treatment increased ceramide levels equally in cells that do (OV177) and do not (OV202) rely on caspase-8 to initiate apoptosis. These results indicate that synthetic retinoids can use caspase-8 as an initiating caspase, but they also indicate unexpected heterogeneity in caspase activation pathways among closely related cell lines.