Premium
Targeting nuclear receptor‐mediated cell growth and death in pediatric solid malignancies
Author(s) -
Beard Jordan A,
Chen Taosheng
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.852.11
Subject(s) - nerve growth factor ib , gene knockdown , cancer research , biology , programmed cell death , cell growth , apoptosis , cancer cell , cancer , pediatric cancer , nuclear receptor , carcinogenesis , microbiology and biotechnology , transcription factor , gene , genetics
Nur77, an orphan nuclear receptor, has been shown to be overexpressed in adult cancers when compared to normal cells, indicating a role in proliferation. Nur77 is also implicated in apoptosis. Nuclear‐accumulated Nur77 promotes cell survival, whereas cytoplasmic accumulation promotes cell death. We have found that Nur77 gene and protein are expressed at high levels in pediatric rhabdomyosarcoma cells when compared to human myoblasts, indicating a role in the malignant phenotype of these cells. Pediatric tumor models with higher Nur77 expression were more susceptible to cell death when treated with CD437, indicating potential selectivity to cancer cells. RNAi knockdown of Nur77 decreased the ability of CD437 to activate caspase‐3/7, indicating a Nur77‐dependent mechanism. Knockdown of Nur77 reduced the growth of osteosarcoma cells demonstrating a role in proliferation. Immunohistochemical analyses of tumor tissues show that Nur77 is expressed in clinical cases when compared to normal tissue, implicating Nur77 in the pathogenesis of these pediatric malignancies. These data suggest that the Nur77 pathway represents an ideal target for pediatric cancer therapy due to the differential expression in normal and cancer cells. High‐throughput and high‐content screening assays are currently being developed to identify compounds that induce Nur77‐mediated cell death in pediatric cancer models.