Src kinase family inhibitor PP2 induces aggregation and detachment of neuroblastoma cells and inhibits cell growth in a PI3 kinase/Akt pathway-independent manner.

ABSTRACT

PURPOSE: Neuroblastoma (NB) is one of the most common extracranial solid tumors in children and is known for its clinical and biological heterogeneity. The aim of this study is to reveal the functional role of src family kinases in the biological behavior of NB by inhibiting their kinase activities with a specific inhibitor, PP2 (4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine). METHODS: NB cell lines (SH-SY5Y, IMR32, RT-BM-1, CHP134, NLF, and LA-N-5) were treated with 0.1-10 µM of PP2. Morphological changes, cell growth, and cell death were assessed, as well as all-trans retinoic acid (ATRA)-induced neuronal differentiation and epidermal growth factor (EGF)-induced proliferation. RESULTS: At 24 h after PP2 treatment, NB cell lines showed drastic cell aggregation. PP2 also inhibited cell growth of NB in a dose-dependent manner. Apoptosis was detected in these cells. ATRA-induced neuronal differentiation of RT-BM-1 was not affected by PP2. PP2 reduced the proliferative effect of EGF. EGF-induced rapid activation of Akt, which was not blocked by PP2 treatment, suggesting that the cellular events triggered by PP2 were independent to PI3 kinase/Akt signaling pathway. CONCLUSION: Our data suggests that src family kinases promote cell survival/proliferation and reduces cell aggregation of NBs. Src family kinase inhibitors may be good candidates for a novel molecular target therapy.