Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cells
Retinoids induced astrocytic differentiation with down regulation of telomerase activity and enhanced sensitivity to taxol for apoptosis in human glioblastoma T98G and U87MG cells
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DOI：
10.1007/s11060-007-9485-1
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发表时间：
2008-03-01
影响因子：
3.9
通讯作者：
Ray, Swapan K.
中科院分区：
文献类型：
--
作者：
Das, Arabinda;Banik, Naren L.;Ray, Swapan K.
我们推测，维甲酸诱导分化可以增加微管结合药物紫杉醇对人胶质母细胞瘤T98G和U87 MG细胞凋亡的敏感性。1MU全反式维甲酸(ATRA)或1MM13-顺式维甲酸(13-CRA)处理细胞7d，可诱导星形胶质细胞分化，胶质纤维酸性蛋白(GFAP)过表达，端粒酶表达和活性下调，从而增加对TXL诱导细胞凋亡的敏感性。TXL诱导胶质母细胞瘤细胞产生ROS，诱导p38丝裂原活化蛋白激酶(MAPK)的磷酸化，激活氧化还原敏感的c-Jun NH2末端激酶1(JNK1)通路。此外，TXL还能激活Raf-1蛋白，使抗细胞凋亡的Bcl2蛋白失活。细胞凋亡的事件包括Bax表达增加，Bcl2和含BIRC的杆状病毒抑制蛋白(IAP)重复序列蛋白表达下调，线粒体释放细胞色素c和Smac进入胞浆，细胞内游离[Ca~(2+)]升高，以及Calain、caspase-9和caspase-3的激活。Caspase-3裂解的caspase激活的DNA酶抑制物(ICAD)活性增加，释放并将CAD转移到细胞核进行DNA碎裂。用特定的抑制剂处理细胞，证实了应激信号转导通路、钙蛋白酶和caspase-3的蛋白水解酶活性参与了细胞的凋亡。综上所述，我们的结果提示，维甲酸(ATRA或13-CRA)诱导星形胶质细胞分化，并下调端粒酶活性，以增加对TXL的敏感性，促进胶质母细胞瘤细胞的凋亡。因此，维甲酸联合TXL可能是控制胶质母细胞瘤生长的有效治疗策略。
We hypothesized that induction of differentiation with retinoid could increase sensitivity to microtubule-binding drug taxol (TXL) for apoptosis in human glioblastoma T98G and U87MG cells. Treatment of cells with 1 mu M all-trans retinoic acid (ATRA) or 1 mu M 13-cis retinoic acid (13-CRA) for 7 days induced astrocytic differentiation, overexpression of glial fibrillary acidic protein (GFAP), and also down regulated telomerase expression and activity, thereby increased sensitivity to TXL for apoptosis. Treatment of glioblastoma cells with TXL triggered production of reactive oxygen species (ROS), induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), and activated the redox-sensitive c-Jun NH2-terminal kinase 1 (JNK1) pathway. Moreover, TXL activated Raf-1 kinase for phosphorylation and inactivaion of anti-apoptotic Bcl-2 protein. The events of apoptosis included increase in expression of Bax, down regulation of Bcl-2 and baculoviral inhibitor-of-apoptosis protein (IAP) repeat containing (BIRC) proteins, mitochondrial release of cytochrome c and Smac into the cytosol, increase in intracellular free [Ca2+], and activation of calpain, caspase-9, and caspase-3. Increased activity of caspase-3 cleaved inhibitor of caspase-activated DNase (ICAD) to release and translocate CAD to the nucleus for DNA fragmentation. Involvement of stress signaling kinases and proteolytic activities of calpain and caspase-3 in apoptosis was confirmed by pretreating cells with specific inhibitors. Taken together, our results suggested that retinoid (ATRA or 13-CRA) induced astrocytic differentiation with down regulation of telomerase activity to increase sensitivity to TXL to enhance apoptosis in glioblastoma cells. Thus, combination of retinoid and TXL could be an effective therapeutic strategy for controlling the growth of glioblastoma.