title: N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines.
abstract: 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.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
authors.forename: M
authors.initials: M
authors.lastname: Cuello
authors.forename: A O
authors.initials: AO
authors.lastname: Coats
authors.forename: I
authors.initials: I
authors.lastname: Darko
authors.forename: S A
authors.initials: SA
authors.lastname: Ettenberg
authors.forename: G J
authors.initials: GJ
authors.lastname: Gardner
authors.forename: M M
authors.initials: MM
authors.lastname: Nau
authors.forename: J R
authors.initials: JR
authors.lastname: Liu
authors.forename: M J
authors.initials: MJ
authors.lastname: Birrer
authors.forename: S
authors.initials: S
authors.lastname: Lipkowitz
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D017313:Fenretinide / Q000633:toxicity*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D047488:Retinoid X Receptors / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D047488:Retinoid X Receptors; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D017313:Fenretinide; D045304:Cytochromes c; D020169:Caspases