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Women's Cancer Program (K.R.K., C.E., L.C.H., C.A.C., S.H.K.), Mayo Clinic Cancer Center; Divisions of Endocrine Research (K.R.K., K.E.D., C.A.C.), Oncology Research (P.A.S., S.H.K.), and Medical Oncology (L.C.H., C.E.), Mayo Clinic; and Department of Molecular Pharmacology (C.R.A., M.P.H., S.H.K.), Mayo Graduate School, Rochester, Minnesota; and John Wayne Cancer Institute at St. John's Health Center, Santa Monica, California (M.C.C.)
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-
, 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.
Address correspondence to: Dr. Kimberly R. Kalli, Endocrine Research Unit, Joseph 5-194, Mayo Clinic and Foundation, 200 First Street S.W., Rochester, MN 55905. E-mail: kalli.kimberly{at}mayo.edu
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