SBF-1, a synthetic steroidal glycoside, inhibits melanoma growth and metastasis through blocking interaction between PDK1 and AKT3
SBF-1, a synthetic steroidal glycoside, inhibits melanoma growth and metastasis through blocking interaction between PDK1 and AKT3
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SBF-1 是一种合成甾体糖苷，通过阻断 PDK1 和 AKT3 之间的相互作用来抑制黑色素瘤生长和转移
DOI：
10.1016/j.bcp.2012.04.006
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发表时间：
2012-07-15
影响因子：
5.8
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
--
作者：
Li, Wanshuai;Song, Ran;Xu, Qiang
在本研究中，我们证明SBF-1是一种合成甾体糖苷，在体外和体内对黑色素瘤细胞具有很强的抗肿瘤活性。 SBF-1 诱导细胞周期停滞，降低 B16BL6 黑色素瘤细胞中各种细胞周期相关蛋白的表达，但不会引起细胞凋亡。 SBF-1 显着抑制 3-磷酸肌醇依赖性蛋白激酶 1 (PDK1) 的激酶活性，从而下调蛋白激酶 B (AKT) 的磷酸化。在三种已知的 PDK1 亚型中，仅与 B16BL6 黑色素瘤细胞中的 AKT3 相互作用，而 SBF-1 几乎完全阻断了这种相互作用。此外，纤连蛋白的粘附和整合素α4的表达以浓度依赖性方式显着降低。 AKT3 的敲低导致整合素 a4 表达和细胞粘附减少。此外，SBF-1在体内抑制黑色素瘤异种移植物的生长并下调Ala的磷酸化。在自发转移的小鼠模型中，1 和 3 μg/kg 的极低剂量的 SBF-1 极大地抑制了黑色素瘤转移至引流腘淋巴结。综上所述，本研究表明小分子化合物SBF-1在体外和体内均具有非常强的抗黑色素瘤活性。其抗肿瘤作用的机制与阻断PDK1和AKT3之间的相互作用有关。 (C) 2012 Elsevier Inc. 保留所有权利。
In the present study, we demonstrate that SBF-1, a synthetic steroidal glycoside, has a strong antitumor activity against melanoma cells in vitro and in vivo. SBF-1 induced cell cycle arrest with a reduced expression of various cell cycle related proteins in B16BL6 melanoma cells without causing apoptosis. SBF-1 dramatically inhibited kinase activity of 3-phosphoinositide dependent protein kinase 1 (PDK1) and thus down-regulated phosphorylation of protein kinase B (AKT). Among three known isoforms of PDK1 only interacted with AKT3 in B16BL6 melanoma cells, and SBF-1 almost completely blocked this interaction. In addition, adhesion to fibronectin and expression of integrin alpha 4 were significantly reduced in a concentration-dependent manner. Knockdown of AKT3 resulted in the decrease in integrin a4 expression and cell adhesion. Moreover, SBF-1 inhibited the growth of melanoma xenografts and down-regulated the phosphorylation of Ala in vivo. In a mouse model of spontaneous metastasis, SBF-1 at very low doses of 1 and 3 mu g/kg enormously inhibited melanoma metastasis into draining popliteal lymph nodes. Taken together, this study shows a small molecular compound SBF-1 with a very strong anti-melanoma activity both in vitro and in vivo. its mechanism underlying such antitumor effect is related to the blockage of the interaction between PDK1 and AKT3. (C) 2012 Elsevier Inc. All rights reserved.