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Gastrin-Releasing Peptide Receptor Silencing Suppresses the Tumorigenesis and Metastatic Potential of Neuroblastoma
Jingbo Qiao, JungHee Kang, Titilope A. Ishola, Piotr G. Rychahou, B. Mark Evers and Dai H. Chung
Proceedings of the National Academy of Sciences of the United States of America
Vol. 105, No. 35 (Sep. 2, 2008), pp. 12891-12896
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25463962
Page Count: 6
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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 G₂/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.
Proceedings of the National Academy of Sciences of the United States of America © 2008 National Academy of Sciences