N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines
| Autor: | Stan Lipkowitz, Seth A. Ettenberg, Mauricio Cuello, Ginger J. Gardner, I Darko, A O Coats, M M Nau, J R Liu, Michael J. Birrer |
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| Rok vydání: | 2004 |
| Předmět: |
Fenretinide
medicine.drug_class Apoptosis DNA Fragmentation TNF-Related Apoptosis-Inducing Ligand medicine Tumor Cells Cultured Humans Retinoid Molecular Biology Caspase Membrane Glycoproteins biology Tumor Necrosis Factor-alpha Cytochrome c Intrinsic apoptosis Ovary Cytochromes c Cell Biology medicine.disease Cell biology Mitochondria Retinoid X Receptors Mitochondrial permeability transition pore Caspases biology.protein Tumor necrosis factor alpha Female Ovarian cancer Apoptosis Regulatory Proteins |
| Zdroj: | Cell death and differentiation. 11(5) |
| ISSN: | 1350-9047 |
| Popis: | The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity. The combination of 4HPR and TRAIL enhanced cleavage of multiple caspases in the death receptor pathway (including the two initiator caspases, caspase-8 and caspase-9). The 4HPR and TRAIL combination leads to mitochondrial permeability transition, significant increase in cytochrome c release, and increased caspase-9 activation. Caspase-9 may further activate caspase-8, generating an amplification loop. Stable overexpression of Bcl-xL abrogates the interaction between 4HPR and TRAIL at the mitochondrial level by blocking cytochrome c release. As a consequence, a decrease in activation of caspase-9, caspase-8, and TRAIL-mediated apoptosis occurs. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by 4HPR is due to the increase in activation of multiple caspases involving an amplification loop via the mitochondrial-death pathway. These findings offer a promising and novel strategy for the treatment of ovarian cancer. |
| Databáze: | OpenAIRE |
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