Chang Qing, Chen Zhengshan, You Jiangfeng, McNutt Michael A, Zhang Ting, Han Zhihui, Zhang Xiaoyan, Gong Encong, Gu Jiang
Department of Pathology, School of Basic Medical Sciences, Peking (Beijing) University Health Science Center, 38 Xueyuan Road, Beijing, 100083, China.
J Neurooncol. 2007 Sep;84(3):263-7. doi: 10.1007/s11060-007-9380-9. Epub 2007 Apr 24.
Medulloblastomas (MBs) are the most common malignant brain tumors of childhood. Antitumor agents promoting long-term survival with limited toxicities are thus far lacking. Preliminary findings suggest that retinoic acid (RA) derivatives (retinoids) exert antitumor effects by inhibiting cell proliferation and inducing cell differentiation, apoptosis, and growth arrest, and RAs have been specifically shown to induce apoptosis in some MB cells. However, there is no conclusive evidence of retinoids inducing cell growth arrest in MBs. The aim of this study is to investigate whether retinoids play a role in cell-cycle arrest of MB cells. All-trans-retinoic acid (ATRA) was selected for these studies as it is known to have the capacity of inducing cell cycle arrest and apoptosis in other types of cancer cells. Three MB cell lines (DAOY, D283 and D341) were subjected to ATRA treatment. The proportions of cells in the G0/G1 phase of cell cycle and in apoptosis were evaluated. The results showed that cell growth arrest, rather than apoptosis, was the main mechanism by which RA inhibited cell proliferation in the MB cell line DAOY, but not in the others (D283 and D341). Decreased expression of CyclinD1 and C-myc which regulate the transition of cell cycle was observed in DAOY cells following drug treatment, suggesting that these genes might be involved in ATRA retardation of cell cycle progression. Expression of RARbeta, a mediator of the action of retinoids, was also induced by RA in DAOY cells, implying that RAR-beta might also be involved in the mechanism of RA-induced cell cycle arrest. In conclusion, we have provided evidence for the first time that RA may induce cell cycle arrest in vitro in DAOY MB cells via inhibition of CyclinD1 or C-myc.
髓母细胞瘤（MBs）是儿童期最常见的恶性脑肿瘤。目前仍缺乏能在毒性有限的情况下促进长期生存的抗肿瘤药物。初步研究结果表明，维甲酸（RA）衍生物（类视黄醇）通过抑制细胞增殖以及诱导细胞分化、凋亡和生长停滞发挥抗肿瘤作用，并且已明确显示RA能在某些MB细胞中诱导凋亡。然而，尚无确凿证据表明类视黄醇能诱导MBs细胞生长停滞。本研究的目的是调查类视黄醇是否在MB细胞的细胞周期停滞中发挥作用。全反式维甲酸（ATRA）被选用于这些研究，因为已知它有能力在其他类型癌细胞中诱导细胞周期停滞和凋亡。对三种MB细胞系（DAOY、D283和D341）进行ATRA处理。评估细胞周期G0/G1期和凋亡细胞的比例。结果表明，细胞生长停滞而非凋亡是RA抑制MB细胞系DAOY细胞增殖的主要机制，但对其他细胞系（D283和D341）并非如此。药物处理后，在DAOY细胞中观察到调节细胞周期转换的细胞周期蛋白D1（CyclinD1）和C-myc表达降低，这表明这些基因可能参与了ATRA对细胞周期进程的阻滞作用。类视黄醇作用的介质维甲酸受体β（RARbeta）的表达在DAOY细胞中也被RA诱导，这意味着RAR-β可能也参与了RA诱导细胞周期停滞的机制。总之，我们首次提供了证据，表明RA可能通过抑制CyclinD1或C-myc在体外诱导DAOY MB细胞的细胞周期停滞。
