Pentagalloylglucose inhibits estrogen receptor α by lysosome-dependent depletion and modulates ErbB/PI3K/Akt pathway in human breast cancer MCF-7 cells
Journal
Molecular Carcinogenesis
Journal Volume
45
Journal Issue
8
Pages
551-560
Date Issued
2006
Author(s)
Abstract
Estrogens and estrogen receptors (ER) play important roles in estrogen-dependent and ER-positive breast cancer development. Inhibitors against estrogen biosynthesis or anti-estrogens have been used in breast cancer treatment for many years. The aim of this study was to determine whether pentagalloylglucose (5GG) has inhibitory effects on ER function. In the present study, we found that 5GG significantly reduced the growth of estrogen-responsive human breast cancer MCF-7 cells, and suppressed the phosphorylation and protein level of estrogen receptor α (ERα). Interestingly, 5GG decreased ERα protein levels by promoting the degradation of ERα protein in the lysosome. The ERα can be activated through a ligand-dependent and/or a ligand-independent pathway. The activated Akt kinase was shown to directly phosphorylate ERα at its serine residues and cause ligand independent activation. Our results showed that 5GG might inhibit the phosphatidylinositol 3-kinase (PI3K)/Akt pathway either through directly inhibiting Akt kinase activity or through inhibiting phosphorylation of the upstream receptor tyrosine kinases. The depletion of ErbB family receptors, including epidermal growth factor receptor (EGFR), ErbB2, and ErbB3, was also observed. 5GG treatment also led to a dose-dependent decrease in the expression of the estrogen-activated cyclin D1 expression. These findings suggested that 5GG might be a useful chemopreventive or therapeutic agent for hormone-dependent breast cancer through suppressing the functions of ERα by lysosome-dependent depletion and modulating the ErbB/ PI3K/Akt pathway. ? 2006 Wiley-Liss, Inc.
Subjects
Akt; Cyclin D1; ERα; ErbB2; Pentagalloylglucose
SDGs
Other Subjects
benzyloxycarbonylleucylleucylleucinal; cyclin D1; estrogen receptor alpha; fulvestrant; glucose pentagallate; phosphatidylinositol 3 kinase; protein kinase B beta; article; breast cancer; cancer cell; cell strain MCF 7; drug effect; enzyme activity; enzyme inhibition; estrogen synthesis; growth inhibition; human; human cell; lysosome; priority journal; protein degradation; protein phosphorylation; tumor growth; 1-Phosphatidylinositol 3-Kinase; Breast Neoplasms; Cell Line, Tumor; Cyclin D1; Estrogen Receptor alpha; Female; Humans; Hydrolyzable Tannins; Lysosomes; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptor, erbB-2; Receptor, erbB-3
Type
journal article