Ascochlorin suppresses TGF-beta 1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells

作者：Cho Hyun Ji; Kang Jeong Han; Jeong Ji Hak; Jeong Yun Jeong; Park Kwan Kyu; Park Yoon Yub; Moon Yong Suk; Kim Hong Tae; Chung Il Kyung; Kim Cheorl Ho; Chang Hyeun Wook; Chang Young Chae^*

来源：Molecular Biology Reports, 2012, 39(4): 4597-4603.

DOI：10.1007/s11033-011-1251-y

• Plasminogen activator inhibitor-1
• Epidermal growth factor receptor
• Matrix metalloproteinase
• Ascochlorin
• Fibrosis

Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor-beta 1 (TGF-beta 1), the growth factor involved in fibrosis, modulates ECM synthesis and accumulation. TGF-beta 1 enhances the production of stimulators of ECM synthesis such as plasminogen activator inhibitor type 1 (PAI-1). As such, PAI-1 expression directly influences the proteolysis, invasion, and accumulation of ECM. It was shown in this study that ascochlorin, a prenylpenl antiobiotic, prevents the expression of profibrotic factors, such as PAI-1 and collagen type I, and that the TGF-beta 1-induced PAI-1 promoter activity is inhibited by ascochlorin. Ascochlorin abolishes the phosphorylation of the EGFR-MEK-ERK signaling pathway to regulate the TGF-beta 1-induced expression of PAI-1 without the inhibition of T beta RII phosphorylation. Furthermore, the MEK inhibitor and EGFR siRNA block PAI-1 expression, and the Raf-1, MEK, and ERK signaling pathways for the regulation of PAI-1 expression. Ascochlorin suppresses the matrix metalloproteinases (MMPs) activity to activate the heparin-binding EGF-like growth factor (HB-EGF), to induce the phosphorylation of EGFR, and the MMPs inhibitor suppresses EGFR phosphorylation and the PAI-1 mRNA levels. These results suggest that ascochlorin prevents the expression of PAI-1 via the inhibition of an EGFR-dependent signal transduction pathway activated by MMPs.

• 出版日期2012-4