Molecular and Cellular Biology, Graduate School of Human Health Science, University of Nagasaki, Siebold, Nagayo, Nagasaki, 851-2195, Japan.
J Neurooncol. 2011 Sep;104(3):705-13. doi: 10.1007/s11060-011-0556-y. Epub 2011 Mar 4.
All-trans retinoic acid (ATRA) plays crucial roles in cell survival and differentiation of neuroblastoma cells. In the present study, we investigated the effects of geranylgeranoic acid (GGA), an acyclic retinoid, on differentiation and tropomyosin-related kinase receptor B (TrkB) gene expression in SH-SY5Y human neuroblastoma cells in comparison with ATRA. GGA induced growth suppression and neural differentiation to the same extent as ATRA. Two variants (145 and 95 kD) of the TrkB protein were dramatically increased by GGA treatment, comparable to the effect of ATRA. Following 6- to 8-day GGA treatment, the effect of GGA on TrkB was reversed after 2-4 days of its removal, whereas the effect of ATRA was irreversible under the same conditions. Both GGA and ATRA upregulated the cellular levels of three major TrkB messenger RNA splice variants in a time-dependent manner. Time-dependent induction of cell cycle-related genes, such as cyclin D1 and retinoblastoma protein, and amplification of the neural progenitor cell marker, brain lipid binding protein, were suppressed by GGA treatment and were completely abolished by ATRA. ATRA and GGA induced retinoic acid receptor β (RARβ) expression, whereas the time-dependent expression of both RARα and RARγ was abolished by ATRA, but not by GGA. Our results suggest that GGA may be able to restore neuronal properties of SH-SY5Y human neuroblastoma cells in a similar but not identical way to ATRA.
全反式视黄酸（ATRA）在神经母细胞瘤细胞的存活和分化中起着至关重要的作用。在本研究中，我们研究了无环视黄酸（GGA）对分化和原肌球蛋白相关激酶受体 B（TrkB）基因表达的影响，并与 ATRA 进行了比较。GGA 诱导的生长抑制和神经分化与 ATRA 相同。GGA 处理后，TrkB 蛋白的两种变体（145 和 95 kD）显著增加，与 ATRA 的作用相当。经过 6-8 天的 GGA 处理后，在去除 GGA 2-4 天后，GGA 对 TrkB 的作用被逆转，而在相同条件下，ATRA 的作用是不可逆的。GGA 和 ATRA 均可时间依赖性地上调三种主要 TrkB 信使 RNA 剪接变体的细胞水平。细胞周期相关基因，如周期蛋白 D1 和视网膜母细胞瘤蛋白的时间依赖性诱导，以及神经前体细胞标志物脑脂质结合蛋白的扩增，均被 GGA 处理抑制，并被 ATRA 完全消除。ATRA 和 GGA 诱导视黄酸受体β（RARβ）表达，而 RARα 和 RARγ 的时间依赖性表达均被 ATRA 消除，但不受 GGA 影响。我们的结果表明，GGA 可能能够以类似于 ATRA 的方式但不完全相同的方式恢复 SH-SY5Y 人神经母细胞瘤细胞的神经元特性。
