Retinoid receptor-dependent and -independent effects of N-(4-hydroxyphenyl)retinamide in F9 embryonal carcinoma cells

Fenretinide {N-[4-hydroxyphenyl]retinamide (4HPR)} is a retinoid analogue w ith antitumor and chemopreventive activities. The mechanism of action of 4H PR is not fully understood, but it is hypothesized that this compound acts independently of the nuclear retinoid receptor pathway. To test this hypoth esis directly, we have analyzed the activity of 4HPR on a panel of F9 embry onal carcinoma cell lines, which includes wild-type and mutant lines that l ack expression of retinoic acid receptor gamma, retinoid X receptor alpha o r both. 4HPR (10 mu M) treatment resulted in a rapid induction of cell deat h in F9 cells, which was responsible for their near elimination by 48 h. Th is effect occurred in the receptor-null cell lines as well. Treatment of th e wild-type cells for 4 days with 1 mu M 4HPR also resulted in a primitive endodermal differentiated phenotype that is normally seen upon all-trans-re tinoic acid treatment and is characterized by the up-regulation of laminin B1 and type IV collagen. This differentiation response did not occur in the receptor-null cells. Therefore, two distinct effects of 4HPR were identifi ed in this system: a rapid induction of cell death and a slower induction o f differentiation, which are likely to be receptor independent and dependen t, respectively.