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Differential effects of 9-cis and all-trans retinoic acid on the induction of retinoic acid receptor-beta and cellular retinoic acid-binding protein II in human neuroblastoma cells.

ABSTRACT: The objective of this study was to compare the properties of 9-cis and all-trans retinoic acid with respect to the induction of expression of retinoic acid receptor beta (RAR-beta) and cellular retinoic acid-binding protein (CRABP) II in human neuroblastoma SH SY 5Y cells. RAR-beta and CRABP II mRNA was induced by both all-trans and 9-cis retinoic acid in SH SY 5Y cells. Induction was rapid, detectable within 2-4 h, and inhibited by actinomycin D. Time-courses of induction for RAR-beta and CRABP II differed: RAR-beta mRNA levels reached a maximum 4-6 h after adding all-trans or 9-cis retinoic acid, whereas CRABP II mRNA levels increased over at least 18 h. These differences were attributed to the longer half-life of CRABP II mRNA (20 h) compared with RAR-beta mRNA (3.9 h). The dose-response characteristics of all-trans and 9-cis retinoic acid were different: all-trans was effective at nanomolar concentrations, whereas 10-fold higher levels of 9-cis retinoic acid were required to achieve comparable induction of RAR-beta and CRABP II. Conversely, at high concentrations, 9-cis retinoic acid gave a greater induction of RAR-beta and CRABP II than all-trans. The induction of RAR-beta and CRABP II by all-trans retinoic acid was maintained in the subsequent absence of all-trans retinoic acid, whereas induction by 9-cis retinoic acid was dependent on its continued presence in the culture medium. These results suggest that, at high concentrations, 9-cis retinoic acid may produce its transcriptional effects via retinoid X receptor (RXR) homodimers. This has implications for the cellular functions of 9-cis retinoic acid and its use as a biological response modifier.

SUBMITTER: Redfern CP

PROVIDER: S-EPMC1137464 | biostudies-other | 1994 Nov

REPOSITORIES: biostudies-other

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Project description:PurposeNeuroblastoma is an embryonic childhood cancer with high mortality. 13-cis retinoic acid (13-cisRA) improves survival for some patients, but many recur, suggesting clinical resistance. The mechanism of resistance and the normal differentiation pathway are poorly understood. Three-amino-acid loop extension (TALE) family genes are master regulators of differentiation. Because retinoids promote differentiation in neuroblastoma, we evaluated TALE family gene expression in neuroblastoma.Experimental designWe evaluated expression of TALE family genes in RA-sensitive and -resistant neuroblastoma cell lines, with and without 13-cisRA treatment, identifying genes whose expression correlates with retinoid sensitivity. We evaluated the roles of one gene, PBX1, in neuroblastoma cell lines, including proliferation and differentiation. We evaluated PBX1 expression in primary human neuroblastoma samples by qRT-PCR, and three independent clinical cohort microarray datasets.ResultsWe confirmed that induction of PBX1 expression, and no other TALE family genes, was associated with 13-cisRA responsiveness in neuroblastoma cell lines. Exogenous PBX1 expression in neuroblastoma cell lines, mimicking induced PBX1 expression, significantly impaired proliferation and anchorage-independent growth, and promoted RA-dependent and -independent differentiation. Reduced PBX1 protein levels produced an aggressive growth phenotype and RA resistance. PBX1 expression correlated with histologic neuroblastoma subtypes, with highest expression in benign ganglioneuromas and lowest in high-risk neuroblastomas. High PBX1 expression is prognostic of survival, including in multivariate analysis, in the three clinical cohorts.ConclusionsPBX1 is an essential regulator of differentiation in neuroblastoma and potentiates retinoid-induced differentiation. Neuroblastoma cells and tumors with low PBX1 expression have an immature phenotype with poorer prognosis, independent of other risk factors.

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Differential effects of 9-cis and all-trans retinoic acid on the induction of retinoic acid receptor-beta and cellular retinoic acid-binding protein II in human neuroblastoma cells.

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