title: N-Myc down regulation induced differentiation, early cell cycle exit, and apoptosis in human malignant neuroblastoma cells having wild type or mutant p53.
abstract: Neuroblastomas, which mostly occur in children, are aggressive metastatic tumors of the sympathetic nervous system. The failure of the previous therapeutic regimens to target multiple components of N-Myc pathway resulted in poor prognosis. The present study investigated the efficacy of the combination of N-(4-hydroxyphenyl) retinamide (4-HPR, 0.5 microM) and genistein (GST, 25 microM) to control the growth of human neuroblastoma cells (SH-SY5Y and SK-N-BE2) harboring divergent molecular attributes. Combination of 4-HPR and GST down regulated N-Myc, Notch-1, and Id2 to induce neuronal differentiation. Transition to neuronal phenotype was accompanied by increase in expression of e-cadherin. Induction of neuronal differentiation was associated with decreased expression of hTERT, PCNA, survivin, and fibronectin. This is the first report that combination of 4-HPR and GST mediated reactivation of multiple tumor suppressors (p53, p21, Rb, and PTEN) for early cell cycle exit (due to G1/S phase arrest) in neuroblastoma cells. Reactivation of tumor suppressor(s) repressed N-Myc driven growth factor mediated angiogenic and invasive pathways (VEGF, b-FGF, MMP-2, and MMP-9) in neuroblastoma. Repression of angiogenic factors led to the blockade of components of mitogenic pathways [phospho-Akt (Thr 308), p65 NF-kappaB, and p42/44 Erk 1/2]. Taken together, the combination of 4-HPR and GST effectively blocked survival, mitogenic, and angiogenic pathways and activated proteases for apoptosis in neuroblastoma cells. These results suggested that combination of 4-HPR and GST could be effective for controlling the growth of heterogeneous human neuroblastoma cell populations.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC 29209, USA.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Janardhanan
authors.forename: Naren L
authors.initials: NL
authors.lastname: Banik
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Ray
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D017313:Fenretinide / Q000494:pharmacology; D005434:Flow Cytometry; D016158:Genes, p53; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics / Q000473:pathology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D017313:Fenretinide; D005982:Glutathione Transferase