Gastrin-releasing peptide receptor silencing suppresses the tumorigenesis and metastatic potential of neuroblastoma
| Autor: | B. Mark Evers, Titilope A. Ishola, Jingbo Qiao, Junghee Kang, Dai H. Chung, Piotr G. Rychahou |
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| Rok vydání: | 2008 |
| Předmět: |
Male
Cell cycle checkpoint Down-Regulation Mice Nude Biology Cell morphology Mice Neuroblastoma Phosphatidylinositol 3-Kinases Cell surface receptor Cell Line Tumor Gastrin-releasing peptide Cell Adhesion medicine Animals Humans Gene Silencing Neoplasm Metastasis Protein kinase B PI3K/AKT/mTOR pathway Cell Proliferation Cell Size Ribosomal Protein S6 Multidisciplinary Cell growth Ribosomal Protein S6 Kinases 70-kDa Biological Sciences medicine.disease Molecular biology Gene Expression Regulation Neoplastic Receptors Bombesin Gastrin-Releasing Peptide Cancer research Proto-Oncogene Proteins c-akt hormones hormone substitutes and hormone antagonists |
| Zdroj: | Proceedings of the National Academy of Sciences. 105:12891-12896 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0711861105 |
| Popis: | Neuroblastoma accounts for nearly 15% of all pediatric cancer-related deaths. We have previously shown that gastrin-releasing peptide (GRP) stimulates neuroblastoma growth, and that its cell surface receptor, GRP-R, is overexpressed in advanced-stage human neuroblastomas; however, the effects of GRP/GRP-R on tumorigenesis and metastasis in vivo are not clearly elucidated. In the present study, we found that GRP-R knockdown in the aggressive cell line BE(2)-C induced cell morphology changes, reduced cell size, decreased cell proliferation, and inhibited DNA synthesis, corresponding to cell cycle arrest at G 2 /M phase. Activated Akt, a crucial regulator of cell survival and metastasis, was down-regulated by GRP-R silencing. In addition, expression of p -p70S6K and its downstream target molecule S6, key regulators of protein synthesis and cell metabolism, were also significantly decreased by GRP-R silencing. GRP-R knockdown also up-regulated the expression of tumor suppressor PTEN, the inhibitor of the PI3K/Akt pathway. Furthermore, silencing GRP-R as well as GRP in BE(2)-C cells suppressed anchorage-independent growth in vitro . Conversely, overexpression of GRP-R in less aggressive SK-N-SH neuroblastoma cells resulted in soft agar colony formation, which was inhibited by a GRP-blocking antibody. Moreover, GRP-R deficiency significantly delayed tumor growth and diminished liver metastases in vivo . Our findings demonstrate that GRP and GRP-R have important oncogenic properties beyond their established mitogenic functions. Therefore, GRP-R may be an ideal therapeutic target for the treatment of aggressive neuroblastomas. |
| Databáze: | OpenAIRE |
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