The dual role of BI 2536, a small-molecule inhibitor that targets PLK1, in induction of apoptosis and attenuation of autophagy in neuroblastoma cells

Abstract

Neuroblastoma (NB) is the most common extra-cranial solid tumor in childhood with the overall 5 years' survival less than 40%. Polo-like kinase 1 (PLK1) is a serine/threonine-protein kinase expressed during mitosis and over expressed in multiple cancers, including neuroblastoma. We found that higher PLK1 expression related to poor outcome of NB patients. BI2536, a small molecule inhibitor against PLK1, significantly reduced cell viability in a panel of NB cell lines, with IC50 less than 100 nM. PLK1 inhibition by BI 2536 treatment induced cell cycle arrest at G₂/M phase and cell apoptosis in NB cells. Realtime PCR array revealed the PLK1 inhibition related genes, such as BIRC7, TNFSF10, LGALS1 and DAD1 <i>et al</i>. Moreover, autophagy activity was investigated in the NB cells treated with BI 2536. BI 2536 treatment in NB cells increased LC3-II puncta formation and LC3-II expression. Formation of autophagosome induced by BI 2536 was observed by transmission electron microscopy. However, BI2536 abrogated the autophagic flux in NB cells by reducing SQSTM1/p62 expression and AMPKα^T172 phosphorylation. These results provide new clues for the molecular mechanism of cell death induced by BI 2536 and suggest that BI 2536 may act as new candidate drug for neuroblastoma.