The regulation of receptor trafficking to the cell surface and its effect on responses of target cells to growth factors and hormones remain poorly understood. Initial evidence has been recently obtained using cancer cells that surface expression of the epidermal growth factor receptor (EGFR) is dependent on its association with progesterone receptor membrane component 1 (PGRMC1). Estrogen inhibition of oocyte maturation (OM) in zebrafish is mediated through G-protein-coupled estrogen membrane receptor 1 (Gper1) and involves activation of Egfr. Therefore, in this study, the potential roles of Pgrmc1 in the cell surface expression and functions of Egfr in normal cells were investigated in this in vitro OM model of Egfr action using an inhibitor of PGMRC1 signaling, AG205. A single ∼60 kDa protein band, which corresponds to the size of the Pgrmc1 dimer, was detected on plasma membranes of fully grown oocytes by western blotting. Co-treatment with the PGRMC1 inhibitor AG205 (20 μM) blocked the inhibitory effects of 100 nM estradiol-17β and the GPER agonist, G-1, on spontaneous maturation of denuded zebrafish oocytes. Moreover, reversal of these estrogen effects on OM by the EGFR inhibitors AG1478 and AG825 (50 μM) was prevented by co-incubation with the PGRMC1 inhibitor. Inhibition of Pgrmc1 signaling with AG205 also caused a decrease in Egfr-dependent signaling and Egfr expression on oocyte cell membranes. These results indicate that maintenance of Pgrmc1 signaling is required for Egfr expression on zebrafish oocyte cell membranes and for conserving the functions of Egfr in maintaining meiotic arrest through estrogen activation of Gper.

2010-01-01·Photochemistry and photobiology3区 · 生物学

Degradation of HER2 Receptor Through Hypericin‐mediated Photodynamic Therapy

3区 · 生物学

Article

作者: Peter Fedorocko ; Rastislav Jendzelovský ; Jaromír Mikes ; Ján Koval ; Martin Kello ; Peter Solár

Abstract:

Current treatment of breast cancer is often affected by resistance to therapeutics, for which the human epidermal growth factor receptor 2 (HER2) may be responsible. Here, we report for the first time the use of hypericin‐mediated photodynamic therapy (HY‐PDT) in combination with a selective HER2 inhibitor (AG 825) on SKBR‐3, a HER2 overexpressing human breast adenocarcinoma cell line. The results demonstrate that HY‐PDT is able to degrade HER2 with an impact on its signaling cascade. Combination with AG 825 resulted in increased apoptosis induction, total degradation of HER2 and inhibition of colony formation. Downregulation of HSP90, Mcl‐1, Bcl‐xL and upregulation of Bax was also observed. This knowledge provides the basis for the possible application of HY‐PDT in preclinical and clinical models of breast cancer treatment.

2010-01-01·World journal of gastroenterology3区 · 医学

High expression of ErbB2 contributes to cholangiocarcinoma cell invasion and proliferation through AKT/p70S6K

3区 · 医学

Article

作者: Warapen Treekitkarnmongkol ; Tuangporn Suthiphongchai

AIM:

To compare the impact of ErbB2 on cell invasion and proliferation in cholangiocarcinoma (CCA) cell lines.

METHODS:

Level of endogenous ErbB2 expression in three CCA cell lines, namely HuCCA-1, KKU-100 and KKU-M213, was determined by real-time reverse-transcriptase polymerase chain reaction. Two ErbB2 inhibitory methods, a small molecule ErbB2 kinase inhibitor (AG825) and siRNA, were used to disrupt ErbB2 function in the cell lines. CCA cell invasion, motility and proliferation under ErbB2-disrupted conditions were detected using Transwell and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. In addition, ErbB2 downstream effectors were investigated by Western blotting analysis.

RESULTS:

Suppression of ErbB2 activity, using a specific kinase inhibitor (AG825), reduced invasion, motility and proliferation of all three CCA cell lines. The ability of this drug to inhibit neoplastic properties (invasion, motility and proliferation) increased concomitantly with the level of ErbB2 expression. Similarly, knockdown of ErbB2 level by siRNA inhibited cell invasion and proliferation of KKU-M213, a high-ErbB2-expressing cell, better than those of the lower-ErbB2-expressing cells, HuCCA-1 and KKU-100. Thus, both inhibitory methods indicated that there is more ErbB2-dependency for malignancy of the high-ErbB2-expressing cell, KKU-M213, than for that of low-ErbB2-expressing ones. In addition, interrupting ErbB2 activity decreased phosphorylation of AKT and p70S6K, but not extracellular signal-regulated kinase 1/2, in the high-ErbB2-expressing CCA cell line.

CONCLUSION:

Our data indicated that high ErbB2 expression enhances CCA invasion, motility and proliferation via the AKT/p70S6K pathway, which suggests the possibility of targeting these molecules for CCA therapy.

100 项与 AG825 相关的药物交易

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