title: PI3K/AKT and ERK regulate retinoic acid-induced neuroblastoma cellular differentiation.
abstract: 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.
authors: Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors: Jingbo
authors: J
authors: Qiao
authors: Pritha
authors: P
authors: Paul
authors: Sora
authors: S
authors: Lee
authors: Lan
authors: L
authors: Qiao
authors: Erlena
authors: E
authors: Josifi
authors: Joshua R
authors: JR
authors: Tiao
authors: Dai H
authors: DH
authors: Chung
mesh_terms: D002454:Cell Differentiation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D009447:Neuroblastoma / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases