BAG-1 promotes apoptosis induced by N-(4-hydroxyphenyl)retinamide in humancervical carcinoma cells

N-(4-hydroxyphenyl)retinamide (4-HPR) is a synthetic apoptosis-inducing ret inoid with cancer chemopreventive properties and lower toxicity than all-tr ans 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 in hibit 4-HPR-induced apoptosis in the C33A cervical carcinoma cell line. Sur prisingly, although it inhibited apoptosis induced by five different apopto tic stimuli, overexpression of BAG-1 enhanced apoptosis induced by 4-HPR, p roducing a 2.5-fold lower IC50 of 4-HPR. The effects of BAG-1 on 4-HPR-indu ced apoptosis were mediated by enhancing the caspase-3 activation pathway. Deletion mutation experiments showed that the central ubiquitin homology do main of BAG-1 protein was necessary for its promotion of 4-HPR-induced apop tosis, whereas its C-terminal Hsp70/Hsc70-interacting domain was required f or its inhibition of staurosporine-induced apoptosis. These in vitro result s suggest that the effectiveness of 4-HPR against the development of malign ancy may be due to the overexpression of BAG-1 in cancer cells. (C) 2000 Ac ademic Press.