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, Dai H. Chung

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)12891-12896
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number35
DOIs
StatePublished - Sep 2 2008

Keywords

  • Akt
  • Anchorage independence
  • Metastasis
  • RNAi

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Gastrin-releasing peptide receptor silencing suppresses the tumorigenesis and metastatic potential of neuroblastoma'. Together they form a unique fingerprint.

Cite this