Resibufogenin Induces G1-Phase Arrest through the Proteasomal Degradation of Cyclin D1 in Human Malignant Tumor Cells.
Resibufogenin Induces G1-Phase Arrest through the Proteasomal Degradation of Cyclin D1 in Human Malignant Tumor Cells.
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DOI：
10.1371/journal.pone.0129851
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sakai T
中科院分区：
文献类型：
--
作者：
Ichikawa M;Sowa Y;Iizumi Y;Aono Y;Sakai T
华产素是一种从干蟾皮中提取的中药，在中国已被用于各种癌症的临床研究。脂蟾毒配基是华蟾素的一种成分，属于蟾蜍二烯内酯类。脂蟾毒配基已显示出对癌细胞的抗增殖作用。然而，脂蟾毒配基的分子机制仍不清楚。在这里，我们报告，脂蟾毒配基诱导G1期阻滞与视网膜母细胞瘤（RB）蛋白的低磷酸化和下调细胞周期蛋白D1的表达在人结肠癌HT-29细胞。由于蛋白酶体抑制剂MG 132完全阻断了细胞周期蛋白D1的下调，因此认为脂蟾毒配基对细胞周期蛋白D1表达的抑制是以蛋白酶体依赖的方式进行的。已知糖原合成酶激酶-3 β（GSK-3β）诱导细胞周期蛋白D1的蛋白酶体降解。GSK-3β抑制剂SB 216763可抑制脂蟾毒配基引起的细胞周期蛋白D1的减少。在人肺癌A549细胞中也观察到脂蟾毒配基对细胞周期蛋白D1的影响。这些结果提示脂蟾毒配基的抗增殖作用可能与GSK-3β活化引起cyclin D1降解有关。
Huachansu, a traditional Chinese medicine prepared from the dried toad skin, has been used in clinical studies for various cancers in China. Resibufogenin is a component of huachansu and classified as bufadienolides. Resibufogenin has been shown to exhibit the anti-proliferative effect against cancer cells. However, the molecular mechanism of resibufogenin remains unknown. Here we report that resibufogenin induces G1-phase arrest with hypophosphorylation of retinoblastoma (RB) protein and down-regulation of cyclin D1 expression in human colon cancer HT-29 cells. Since the down-regulation of cyclin D1 was completely blocked by a proteasome inhibitor MG132, the suppression of cyclin D1 expression by resibufogenin was considered to be in a proteasome-dependent manner. It is known that glycogen synthase kinase-3β (GSK-3β) induces the proteasomal degradation of cyclin D1. The addition of GSK-3β inhibitor SB216763 inhibited the reduction of cyclin D1 caused by resibufogenin. These effects on cyclin D1 by resibufogenin were also observed in human lung cancer A549 cells. These findings suggest that the anti-proliferative effect of resibufogenin may be attributed to the degradation of cyclin D1 caused by the activation of GSK-3β.
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影响因子：
10.5
作者：
Diehl, JA;Zindy, F;Sherr, CJ
通讯作者：
Sherr, CJ
影响因子：
6.2
作者：
Meng, Zhiqiang;Yang, Peiying;Shen, Yehua;Bei, Wenying;Zhang, Ying;Ge, Yongqian;Newman, Robert A.;Cohen, Lorenzo;Liu, Luming;Thornton, Bob;Chang, David Z.;Liao, Zongxing;Kurzrock, Razelle
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Kurzrock, Razelle
影响因子：
6.4
作者：
BARTKOVA, J;LUKAS, J;BARTEK, J
通讯作者：
BARTEK, J
影响因子：
56.9
作者：
Thornton, Tina M.;Pedraza-Alva, Gustavo;Rincon, Mercedes
通讯作者：
Rincon, Mercedes
影响因子：
16
作者：
Lin, Douglas I.;Barbash, Olena;Diehl, J. Alan
通讯作者：
Diehl, J. Alan