Abstract
Neuroblastoma (NB) is one of the most common extracranial solid tumors of childhood and accounts for 15% of cancer deaths. Even with the multimodality treatment protocols, the advanced-stage tumor overall 5-year survival rate is less than 50%. Therefore, novel drug therapy targeting cellular signal transduction pathways regulating the apoptotic cascade may be important for the treatment of drug-resistant NB. In our previous studies, we have demonstrated that 5 μM sodium orthovanadate (SOV) induced the apoptosis of SH-SY5Y cells. 17-Allylamino-demethoxygeldanamycin (17-AAG) is a geldanamycin- (GA-) derived heat shock protein 90 (Hsp90) inhibitor, and it has been shown to have potent antitumor activity in head and neck cancers. However, the effect of 17-AAG on the apoptosis of NB cells has not been reported. Therefore, the purpose of this study was to determine the effects of 17-AAG and SOV on the growth and invasion of SH-SY5Y cells in vitro and explore the related mechanism. In this study, we first investigated the antiviability effect of 17-AAG on SH-SY5Y cells, then studied the cell apoptosis and invasion influenced by 17-AAG and SOV, and assessed the role of PIWI-Like2 (PIWIL2) and piRNA-PIWI signaling in it. The results showed that 5 μM 17-AAG inhibited cell growth and viability and induced apoptosis in SH-SY5Y cells. Both 17-AAG and SOV reduced the level of PIWIL2 and Bcl-xl proteins and inhibited the invasion of SH-SY5Y cells. In addition, the combined use of the two drugs had greater effect than the single use of any drug.
Highlights
Neuroblastoma (NB) is one of the most common extracranial solid tumors of childhood and accounts for 15% of cancer deaths [1,2,3]
The results showed that the expression of PIWIL2 and Bcl-xl proteins in SH-SY5Y cells reduced after treatment of 5 μM 17-AAG, 5 μM sodium orthovanadate (SOV), and the mixture of the two drugs (Figure 3(a))
The results showed that 5 μM 17-AAG, 5 μM SOV, and the mixture of 5 μM (17-AAG+SOV) treatment increased the apoptotic rates of SH-SY5Y cells at 24 h, 48 h, and 72 h, compared with those in the control group (∗P < 0:05, ∗∗P < 0:01, Figure 4(b))
Summary
Neuroblastoma (NB) is one of the most common extracranial solid tumors of childhood and accounts for 15% of cancer deaths [1,2,3]. Cases of high-risk NB are associated with frequent relapses and tumors that are resistant to alternative chemotherapy regimens. It is reported that the altered cellular responses to apoptosis are thought to play an important role in drug resistance in high-risk NB [7]. Novel drug therapy targeting cellular signal transduction pathways regulating the apoptotic cascade may be important for the treatment of drug-resistant NB. SH-SY5Y cells were usually used as a model system in vitro to investigate the effect and mechanism of new drugs and provide a basis for the formulation of drug strategy and the treatment of diseases. We focus on the treatment of NB and study the effect of 17-allylamino-demethoxygeldanamycin (17AAG) and sodium orthovanadate (SOV, molecular formula: Na3VO4) on the apoptosis and invasion of SH-SY5Y cells
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