Abstract
BackgroundChemotherapy resistance is the major cause of failure in neuroblastoma (NB) treatment. ATXN3 has been linked to various types of cancer and neurodegenerative diseases; however, its roles in NB have not been established. The aim of our study was to explore the role of ATXN3 in the cell death induced by AKT inhibitor (perifosine or MK-2206) or chemotherapy drugs (etoposide or cisplatin) in NB cells.MethodsThe expressions of ATXN3 and BCL-2 family members were detected by Western blot. Cell survival was evaluated by CCK8, cell confluence was measured by IncuCyte, and apoptosis was detected by flow cytometry. AS and BE2 were treated with AKT inhibitors or chemotherapeutics, respectively.ResultsDownregulation of ATXN3 did not block, but significantly increased the perifosine/MK-2206-induced cell death. Among the BCL-2 family members, the expression of pro-apoptotic protein BIM and anti-proapoptotic protein Bcl-xl expression increased significantly when ATXN3 was down-regulated. Downregulation of BIM protected NB cells from the combination of perifosine/MK-2206 and ATXN3 downregulation. Downregulation of ATXN3 did not increase, but decrease the sensitivity of NB cells to etoposide/cisplatin, and knockdown of Bcl-xl attenuated this decrease in sensitivity.ConclusionDownregulation of ATXN3 enhanced AKT inhibitors (perifosine or MK-2206) induced cell death by BIM, but decreased the cell death induced by chemotherapeutic drugs (etoposide or cisplatin) via Bcl-xl. The expression of ATXN3 may be an indicator in selecting different treatment regimen.
Highlights
Neuroblastoma (NB) derives from developing sympathetic nervous system and is the most common solid pediatric tumors in children
We explored the role of ATXN3 in the cell death induced by AKT inhibitors or chemotherapy drugs in NB cells
AS and BE2 cells transfected with control siRNA or ATXN3 siRNA were treated with perifosine for 48 h, and cell confluence (Figures 1B, C), cell survival (Figures 1D, E), and cell apoptosis (Figures 1F, G) were evaluated by IncuCyte Zoom machine, CCK8 assay, and Annexin V/PI flow cytometry, respectively
Summary
Neuroblastoma (NB) derives from developing sympathetic nervous system and is the most common solid pediatric tumors in children. Patients with low risk always show excellent outcomes; about half of all the NB patients are classified as high-risk group, which is associated with a poor prognosis [2]. Chemotherapy is the most common method for NB patients in the clinic, but chemotherapy drug resistance is the leading cause of failure in NB treatment, highlighting the need for exploring potential therapeutic targets of drug sensitivity and new strategies for NB patients. Chemotherapy resistance is the major cause of failure in neuroblastoma (NB) treatment. The aim of our study was to explore the role of ATXN3 in the cell death induced by AKT inhibitor (perifosine or MK2206) or chemotherapy drugs (etoposide or cisplatin) in NB cells
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