Melino G, Draoui M, Bellincampi L, Bernassola F, Bernardini S, Piacentini M, Reichert U, Cohen P
c/o Department of Experimental Medicine, Istituto Dermopatico dell'Immacolata (IDI-IRCCS), Rome, Tor Vergata, Italy.
Exp Cell Res. 1997 Aug 25;235(1):55-61. doi: 10.1006/excr.1997.3656.
All-trans retinoic acid (RA) reduces human neuroblastoma growth by inducing either differentiation or apoptosis. The apoptotic program in these 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 apoptosis in various in vivo and in vitro systems. In neuroblastoma cells, tTG is detected exclusively in the cells expressing the S-type phenotype and showing an increased apoptosis. The present study was undertaken to identify the retinoid receptors which are involved in the regulation of tTG and apoptosis as well as in the in vitro neuronal differentiation of the human SK-N-BE(2) neuroblastoma cell line. We have previously characterized the retinoid acid receptors expressed in this cell line. In the present study, by using synthetic retinoids selectively activating RAR/RXR isoforms, we have identified the RAR/RXR receptors involved in the induction of either apoptosis or differentiation. We have also studied the effect of the selective RA analogs on tTG activity. We observed that while RARalpha- and RARgamma-selective retinoids alone were able to induce tTG activity, only the combined stimulation of both RARalpha and RARgamma induced apoptosis. Conversely, several combinations of RAR/RXR closely mimicked the differentiation effects 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 RARalpha and RARgamma. These data seem relevant for the reported ability of RARgamma to suppress the clinically malignant tumor phenotype in patients.
全反式维甲酸（RA）通过诱导分化或凋亡来抑制人类神经母细胞瘤的生长。这些细胞中的凋亡程序受RA调控，并与“组织”转谷氨酰胺酶（tTG）的转录诱导平行。tTG是一种蛋白质交联酶，在各种体内和体外系统中，它特异性地积聚在正在经历凋亡的细胞中。在神经母细胞瘤细胞中，仅在表达S型表型且凋亡增加的细胞中检测到tTG。本研究旨在确定参与tTG和凋亡调控以及人类SK-N-BE(2)神经母细胞瘤细胞系体外神经元分化的维甲酸受体。我们之前已经对该细胞系中表达的维甲酸受体进行了表征。在本研究中，通过使用选择性激活RAR/RXR亚型的合成维甲酸，我们确定了参与诱导凋亡或分化的RAR/RXR受体。我们还研究了选择性RA类似物对tTG活性的影响。我们观察到，虽然单独的RARα和RARγ选择性维甲酸能够诱导tTG活性，但只有RARα和RARγ的联合刺激才能诱导凋亡。相反，RAR/RXR的几种组合紧密模拟了全反式维甲酸观察到的分化效应。这些结果表明，与分化不同，人类SK-N-BE(2)神经母细胞瘤细胞中凋亡的诱导受RARα和RARγ的特定控制。这些数据似乎与报道的RARγ抑制患者临床恶性肿瘤表型的能力相关。
