Activation of Three Distinct RXR/RAR Heterodimers Induces Growth Arrest and Differentiation of Neuroblastoma Cells*
- From the ‡Cell and Molecular Biology Section, Pediatric Oncology Branch, NCI, National Institutes of Health, Bethesda, Maryland 20892-1928, §Retinoid Program, SRI International, Menlo Park, California 94025, and ¶The Burnham Institute, La Jolla, California 92037
Abstract
Naturally occurring retinoids, like all-trans retinoic acid and 9-cis retinoic acid, are known to affect proliferation and differentiation of sensitive neuroblastoma cell lines. Cellular responsiveness to retinoic acid depends on its interaction with two distinct classes of receptors, the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs). Both receptor classes have three different subtypes (RARα, RARβ, and RARγ and RXRα, RARβ, and RARγ) that act as ligand-dependent transcription factors. To examine the involvement of the different receptor classes and subtypes in the biological responses of neuroblastoma cells to retinoids, we analyzed the effects of a panel of receptor-selective retinoids on cell growth, differentiation, and gene expression on in vitro cultured KCNR cells. Any association of per se inactive RXR-selective with RAR-selective ligands efficiently regulates growth inhibition, differentiation (neurite extension), and expression of RARβ, TrkB, and N-myc. SR11383 alone, a very potent retinoid, entirely reproduces the pattern of biological responses induced by naturally occurring retinoids. In contrast to other tumor cell lines, the growth of neuroblastoma cell lines is not altered using AP1-antagonistic retinoids. These studies raise the possibility that three distinct RXR/RAR heterodimers mediate the effects of retinoids on neuroblastoma cells through an AP-1 antagonism-independent mechanism.
Footnotes
-
↵* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵‖ To whom correspondence should be addressed: Pediatric Branch, NCI, National Institutes of Health, 10 Center Dr. MSC-1928; Bldg. 10, Rm. 13N240, Bethesda, MD 20892-1928. Tel.: 301-496-1543; Fax: 301-402-0575; E-mail: thielec{at}pbmac.nci.nih.gov.
-
↵1 The abbreviations used are: NB, neuroblastoma; RA, retinoic acid; RAR, retinoic acid receptor; RXR, retinoid X receptor; ATRA, all-trans retinoic acid; 9CRA, 9-cis retinoic acid; RARE, RA-responsive element; FBS, fetal bovine serum; RT, reverse transcription; PCR, polymerase chain reaction; FACS, fluorescence-activated cell sorter; CAT, chloramphenicol acetyltransferase.
-
↵2 G. Giannini, unpublished observation.
-
↵3 C. J. Thiele, unpublished observation.
-
↵4 Y. Kitajima, K. Matsumoto, M. Y. Morrill, C. Gaetano, and C. J. Thiele, submitted for publication.
-
↵5 P. Adamson, Pediatric Branch, NCI, National Institutes of Health. A pediatric phase I trial (92-C-0270D) and pharmacokinetic study of all-trans retinoic acid in combination with interferon α2a and a pediatric phase I trial and pharmacokinetic study (95-C-0030) of LGD1057 (9-cis retinoic acid).
-
- Received June 6, 1997.
- Revision received August 6, 1997.
