Knock-down of Pdcd4 stimulates angiogenesis via up-regulation of angiopoietin-2

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• 作者：Sebastian Krug^a ; Johannes Huth^a ; ^b ; Friederike Gö ; ke^c ; Malte Buchholz^a ; Thomas M. Gress^a ; Rü ; diger Gö ; ke^a ; Brigitte Lankat-Buttgereit^a ; ^{lankatbu@staff.uni-marburg.de}
• 关键词：Pdcd4 ; Tumor suppressor ; Angiogenesis ; Angiopoietin-2
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2012
• 期刊代码：20_01674889
• 类别：bio
• 出版时间：April, 2012
• 卷：1823
• 期：4
• 页码：789-799
• 文件大小：1301 K

摘要

The tumor suppressor Pdcd4 is involved in multiple pathways. Considering its biological action conflicting data in the literature exist and, consequently, our own studies point to a cell type specific action of Pdcd4. In the present study, using several Pdcd4 knock down cell lines we succeeded to identify angiopoietin-2 (Ang-2) as a gene up-regulated on the mRNA and protein level. The subsequent enhanced peptide secretion forced wild type Bon-1 cells in a neoplastic direction demonstrated by increased proliferation and colony formation while cell adhesion was decreased. Most likely, the stimulation of Ang-2 is in part mediated by increased activation of AP-1 but different signal transduction pathways may also be involved since we found opposite activation of PI3K/Akt/mTOR and MAPK7ERK pathways (both known to regulate in Ang-2 expression). Ang-2 is a modulator of vascular remodeling. Therefore, we analyzed the effect of supernatants from Pdcd4 knock-down cell lines on endothelial cells. Again, we detected reduced cell adhesion and increased colony formation. Probably, the most impressive effect was described on tube formation in a model for angiogenesis. Tube length and junctions of endothelial cells treated with conditioned medium from Pdcd4 knock-down cells were considerably increased. Both, up-regulation of Ang-2 and down-regulation of Pdcd4 are described for many tumors. However, this is the first study showing a direct impact of Pdcd4 on Ang-2 levels and, thereby, angiogenesis. Our data suggest a completely new mechanism for Pdcd4 to act as a tumor suppressor rendering Pdcd4 an attractive target for new therapeutic strategies in cancer treatment.