PI3K/AKT and ERK regulate retinoic acid-induced neuroblastoma cellular differentiation.

Qiao J, Paul P, Lee S, Qiao L, Josifi E, Tiao JR, Chung DH
Biochem Biophys Res Commun. 2012 424 (3): 421-6

PMID: 22766505 · PMCID: PMC3668681 · DOI:10.1016/j.bbrc.2012.06.125

Neuroblastoma, the most common extra-cranial solid tumor in infants and children, is characterized by a high rate of spontaneous remissions in infancy. Retinoic acid (RA) has been known to induce neuroblastoma differentiation; however, the molecular mechanisms and signaling pathways that are responsible for RA-mediated neuroblastoma cell differentiation remain unclear. Here, we sought to determine the cell signaling processes involved in RA-induced cellular differentiation. Upon RA administration, human neuroblastoma cell lines, SK-N-SH and BE(2)-C, demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Moreover, cell cycle arrest occurred in G1/G0 phase. The protein levels of cyclin-dependent kinase inhibitors, p21 and p27(Kip), which inhibit cell proliferation by blocking cell cycle progression at G1/S phase, increased after RA treatment. Interestingly, RA promoted cell survival during the differentiation process, hence suggesting a potential mechanism for neuroblastoma resistance to RA therapy. Importantly, we found that the PI3K/AKT pathway is required for RA-induced neuroblastoma cell differentiation. Our results elucidated the molecular mechanism of RA-induced neuroblastoma cellular differentiation, which may be important for developing novel therapeutic strategy against poorly differentiated neuroblastoma.

Copyright © 2012 Elsevier Inc. All rights reserved.

MeSH Terms (10)

Cell Differentiation Extracellular Signal-Regulated MAP Kinases G1 Phase Cell Cycle Checkpoints Humans Neuroblastoma Phosphatidylinositol 3-Kinases Phosphorylation Proto-Oncogene Proteins c-akt Resting Phase, Cell Cycle Tretinoin

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