RETINOIC ACID RECEPTOR-ALPHA AND RECEPTOR-GAMMA MEDIATE THE INDUCTIONOF TISSUE TRANSGLUTAMINASE ACTIVITY AND APOPTOSIS IN HUMAN NEUROBLASTOMA-CELLS

All-trans retinoic acid (RA) reduces human neuroblastoma growth by ind ucing either differentiation or apoptosis. The apoptotic program in th ese cells is regulated by RA and is paralleled by the transcriptional induction of ''tissue'' transglutaminase (tTG). tTG is a protein cross -linking enzyme, which specifically accumulates in cells undergoing ap optosis in various in vivo and in vitro systems. In neuroblastoma cell s, tTG is detected exclusively in the cells expressing the S-type phen otype and showing an increased apoptosis. The present study was undert aken to identify the retinoid receptors which are involved in the regu lation of tTG and apoptosis as well as in the in vitro neuronal differ entiation of the human SK-N-BE(2) neuroblastoma cell line. We have pre viously characterized the retinoid acid receptors expressed in this ce ll line. In the present study, by using synthetic retinoids selectivel y activating RAR/RXR isoforms, we have identified the RAR/RXR receptor s involved in the induction of either apoptosis or differentiation. We have also studied the effect of the selective RA analogs on tTG activ ity. We observed that while RAR alpha- and RAR gamma-selective retinoi ds alone were able to induce tTG activity, only the combined stimulati on of both RAR alpha and RAR gamma induced apoptosis. Conversely, seve ral combinations of RAR/RXR closely mimicked the differentiation effec ts observed with all-trans retinoic acid. These results indicate that, at variance with differentiation, the induction of apoptosis in human SK-N-BE(2) neuroblastoma cells is under the specific control of RAR a lpha and RAR gamma. These data seem relevant for the reported ability of RAR gamma to suppress the clinically malignant tumor phenotype in p atients. (C) 1997 Academic Press.