SBF-1, a synthetic steroidal glycoside, inhibits melanoma growth and metastasis through blocking interaction between PDK1 and AKT3

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• 作者：Wanshuai Li^a ; Ran Song^a ; Xianying Fang^a ; Lu Wang^a ; Wei Chen^a ; Pingping Tang^b ; Biao Yu^b ; ^{byu@mail.sioc.ac.cn} ; Yang Sun^a ; ^{molpharm@163.com} ; Qiang Xu^a ; ^{molpharm@163.com}
• 关键词：SBF-1 ; Melanoma ; PDK-1 ; AKT3 ; Metastasis
• 刊名：Biochemical Pharmacology
• 出版年：2012
• 期刊代码：2_00062952
• 类别：pha
• 出版时间：15 July, 2012
• 卷：84
• 期：2
• 页码：172-181
• 文件大小：1351 K

摘要

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 AKT, 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 伪4 were significantly reduced in a concentration-dependent manner. Knockdown of AKT3 resulted in the decrease in integrin 伪4 expression and cell adhesion. Moreover, SBF-1 inhibited the growth of melanoma xenografts and down-regulated the phosphorylation of AKT in vivo. In a mouse model of spontaneous metastasis, SBF-1 at very low doses of 1 and 3 渭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.