Gambogic acid inhibits tumor cell adhesion by suppressing integrin β1 and membrane lipid rafts-associated integrin signaling pathway.

Abstract

Cell adhesion plays an important role in the steps of cancer metastasis. Regulation of cell-cell (intercellular) and cell-matrix adhesion is a promising strategy for cancer progression. Gambogic acid is a xanthone derived from the resin of the Chinese plant Garciania hanburyi, with potent anti-metastasis activity on highly metastatic cells. The aim of this study was to investigate the function and mechanism of gambogic acid on tumor adhesion. We found that gambogic acid strongly inhibited the adhesion of human cancer cells to fibronectin. This inhibition was associated with the deformation of focal adhesion complex, which was mediated by suppressing the expression of integrin β1 and integrin signaling pathway. In vitro, cell lipid rafts clustering was inhibited following treatment of gambogic acid, which induced the suppression of integrin β1 and focal adhesion complex proteins colocalization within rafts. Moreover, gambogic acid significantly decreased cellular cholesterol content, whereas cholesterol replenishment lessened the inhibitory effect of gambogic acid on cell adhesion. Real-time PCR analysis showed that gambogic acid reduced mRNA levels of hydroxymethylglutaryl-CoA reductase and sterol regulatory element binding protein-2, while increased acetyl-CoA acetyltransferase-1/2. Taken together, these results demonstrate that gambogic acid inhibits cell adhesion via suppressing integrin β1 abundance and cholesterol content as well as the membrane lipid raft-associated integrin function, which provide new evidence for the anti-cancer activity of gambogic acid.

• Authors: Chenglin Li, Na Lu, Qi Qi, Fanni Li, Yun Ling, Yan Chen, Yansu Qin, Zhiyu Li, Haiwei Zhang, Qidong You, Qinglong Guo
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 82 Issue 12 Pg. 1873-83 (Dec 15 2011) ISSN: 1873-2968 [Electronic] England
• PMID: 21946083 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Fibronectins
• Integrin beta1
• Xanthones
• gambogic acid
• Cholesterol

Topics

• Antineoplastic Agents (pharmacology)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cholesterol (metabolism)
• Fibronectins (metabolism)
• Focal Adhesions (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Integrin beta1 (metabolism)
• Membrane Microdomains (drug effects, metabolism)
• Molecular Structure
• Signal Transduction (drug effects)
• Xanthones (pharmacology)