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

Wanshuai Li, Ran Song, Xianying Fang, Lu Wang, Wei Chen, Pingping Tang, Biao Yu*, Yang Sun, Qiang Xu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)172-181
Number of pages10
JournalBiochemical Pharmacology
Volume84
Issue number2
DOIs
StatePublished - Jul 15 2012

Keywords

  • AKT3
  • Melanoma
  • Metastasis
  • PDK-1
  • SBF-1

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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