title: The unhydrolyzable fenretinide analogue 4-hydroxybenzylretinone induces the proapoptotic genes GADD153 (CHOP) and Bcl-2-binding component 3 (PUMA) and apoptosis that is caspase- dependent and independent of the retinoic acid receptor.
abstract: The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) induces apoptosis in a variety of cell lines and has shown promise as an anticancer agent both in vitro and in vivo. The clinical dose of 4-HPR, however, is limited by residual-associated toxicities, indicating a need for a less toxic drug. In this study, we show that 4-hydroxybenzylretinone (4-HBR), the unhydrolyzable analogue of 4-HPR, is effective in producing apoptosis in a variety of 4-HPR-sensitive cell lines, including breast cancer, neuroblastoma, and leukemia cells. We also show through the use of a pan-caspase inhibitor that this 4-HBR-induced apoptosis is dependent, at least in part, on caspase activity. 4-HBR is shown to exhibit binding to the retinoic acid receptors (RAR) at concentrations necessary to induce cell death and induces expression of all-trans-retinoic acid-responsive genes that can be blocked by a RAR pan-antagonist. However, through the use of this RAR pan-antagonist, 4-HBR-induced apoptosis and cell death is shown to be independent of the RAR signaling pathway. To further characterize the mechanism of action of 4-HBR, expression of the endoplasmic reticulum stress-induced genes GADD153 and Bcl-2-binding component 3 was examined. These mRNAs are shown to be rapidly induced in 4-HBR-treated and 4-HPR-treated breast cancer cells, and this up-regulation is also shown to be independent of the RARs. These results suggest that a stress-mediated apoptotic cascade is involved in the mechanism of action of these retinoids.
authors.affiliation: Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Allyson L
authors.initials: AL
authors.lastname: Anding
authors.forename: Jason S
authors.initials: JS
authors.lastname: Chapman
authors.forename: Derek W
authors.initials: DW
authors.lastname: Barnett
authors.forename: Robert W
authors.initials: RW
authors.lastname: Curley
authors.forename: Margaret
authors.initials: M
authors.lastname: Clagett-Dame
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017313:Fenretinide / Q000031:analogs & derivatives*; D018922:HL-60 Cells; D006801:Humans; D006868:Hydrolysis; D007938:Leukemia / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000096:biosynthesis*; D014801:Vitamin A / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C451736:4-hydroxybenzylretinone; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D012176:Retinoids; D014801:Vitamin A; D051742:Transcription Factor CHOP; D017313:Fenretinide; D020169:Caspases