BAG-1 promotes apoptosis induced by N-(4-hydroxyphenyl)retinamide in human cervical carcinoma cells.
N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic apoptosis-inducing retinoid with cancer chemopreventive properties and lower toxicity than all-trans retinoic acid. BAG-1 is an antiapoptotic gene that is overexpressed in cervical and other cancers. In this study, we examined whether BAG-1 can inhibit 4-HPR-induced apoptosis in the C33A cervical carcinoma cell line. Surprisingly, although it inhibited apoptosis induced by five different apoptotic stimuli, overexpression of BAG-1 enhanced apoptosis induced by 4-HPR, producing a 2.5-fold lower IC(50) of 4-HPR. The effects of BAG-1 on 4-HPR-induced apoptosis were mediated by enhancing the caspase-3 activation pathway. Deletion mutation experiments showed that the central ubiquitin homology domain of BAG-1 protein was necessary for its promotion of 4-HPR-induced apoptosis, whereas its C-terminal Hsp70/Hsc70-interacting domain was required for its inhibition of staurosporine-induced apoptosis. These in vitro results suggest that the effectiveness of 4-HPR against the development of malignancy may be due to the overexpression of BAG-1 in cancer cells.
Yang
X
X
Division of Basic Medical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, A1B 3V6, Canada.
Hao
Y
Y
Ding
Z
Z
Pater
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004268:DNA-Binding Proteins; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D017434:Protein Structure, Tertiary; D019311:Staurosporine / Q000494:pharmacology; D014157:Transcription Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D017313:Fenretinide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D019311:Staurosporine