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

Abstract

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 α4 were significantly reduced in a concentration-dependent manner. Knockdown of AKT3 resulted in the decrease in integrin α4 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 μg/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.

• Authors: Wanshuai Li, Ran Song, Xianying Fang, Lu Wang, Wei Chen, Pingping Tang, Biao Yu, Yang Sun, Qiang Xu
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 84 Issue 2 Pg. 172-81 (Jul 15 2012) ISSN: 1873-2968 [Electronic] England
• PMID: 22525724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cholestenones
• Enzyme Inhibitors
• PDK1 protein, human
• Pdk1 protein, mouse
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• SBF-1 compound
• Saponins
• Integrin alpha4
• AKT3 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Base Sequence
• Cell Cycle Checkpoints (drug effects)
• Cell Proliferation (drug effects)
• Cholestenones (pharmacology)
• Dose-Response Relationship, Drug
• Down-Regulation
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (pharmacology)
• Female
• Humans
• Integrin alpha4 (metabolism)
• Melanoma (drug therapy, metabolism, pathology)
• Melanoma, Experimental (drug therapy, pathology)
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Phosphorylation
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyruvate Dehydrogenase Acetyl-Transferring Kinase
• Saponins (pharmacology)