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 with antitumor and chemopreventive activities. The mechanism of action of 4HPR is not fully understood, but it is hypothesized that this compound acts independently of the nuclear retinoid receptor pathway. To test this hypothesis directly, we have analyzed the activity of 4HPR on a panel of F9 embryonal carcinoma cell lines, which includes wild-type and mutant lines that lack expression of retinoic acid receptor gamma, retinoid X receptor alpha, or both. 4HPR (10 microM) treatment resulted in a rapid induction of cell death in F9 cells, which was responsible for their near elimination by 48 h. This effect occurred in the receptor-null cell lines as well. Treatment of the wild-type cells for 4 days with 1 microM 4HPR also resulted in a primitive endodermal differentiated phenotype that is normally seen upon all-trans-retinoic 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 identified in this system: a rapid induction of cell death and a slower induction of differentiation, which are likely to be receptor independent and dependent, respectively.
Clifford
J L
JL
Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. reksohad@ix.netcom.com
Menter
D G
DG
Wang
M
M
Lotan
R
R
Lippman
S M
SM
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018236:Carcinoma, Embryonal / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D017313:Fenretinide / Q000494:pharmacology*; D051379:Mice; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D047488:Retinoid X Receptors; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000097768:Retinoic Acid Receptor gamma
D000970:Antineoplastic Agents; D017313:Fenretinide; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D000097768:Retinoic Acid Receptor gamma