Heterogeneous Role of Caspase-8 in Fenretinide-Induced Apoptosis in Epithelial Ovarian Carcinoma Cell Lines

Kimberly R. Kalli, Kathryn E. Devine, Myles C. Cabot, Christina R. Arnt, Michael P. Heldebrant, Phyllis A. Svingen, Charles Erlichman, Lynn C. Hartmann, Cheryl A. Conover, Scott H. Kaufmann

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1434-1443
Number of pages10
JournalMolecular pharmacology
Volume64
Issue number6
DOIs
StatePublished - Dec 1 2003

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Kalli, K. R., Devine, K. E., Cabot, M. C., Arnt, C. R., Heldebrant, M. P., Svingen, P. A., Erlichman, C., Hartmann, L. C., Conover, C. A., & Kaufmann, S. H. (2003). Heterogeneous Role of Caspase-8 in Fenretinide-Induced Apoptosis in Epithelial Ovarian Carcinoma Cell Lines. Molecular pharmacology, 64(6), 1434-1443. https://doi.org/10.1124/mol.64.6.1434