Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells.
Downregulation of ATXN3 Enhances the Sensitivity to AKT Inhibitors (Perifosine or MK-2206), but Decreases the Sensitivity to Chemotherapeutic Drugs (Etoposide or Cisplatin) in Neuroblastoma Cells.
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DOI：
10.3389/fonc.2021.686898
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发表时间：
2021
影响因子：
4.7
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Gong B;Zhang J;Hua Z;Liu Z;Thiele CJ;Li Z
化疗耐药是神经母细胞瘤（NB）治疗失败的主要原因。ATXN 3与各种类型的癌症和神经退行性疾病有关;然而，它在NB中的作用尚未确定。本研究旨在探讨ATXN 3在AKT抑制剂（perifosine或MK-2206）或化疗药物（etoposide或cisplatin）诱导NB细胞死亡中的作用。Western blot检测ATXN 3和BCL-2家族成员的表达。CCK 8法检测细胞存活率，IncuCyte法检测细胞融合率，流式细胞仪检测细胞凋亡。AS和BE 2分别用AKT抑制剂或化疗药物治疗。ATXN 3的下调不阻断，但显著增加了哌立福新/MK-2206诱导的细胞死亡。在BCL-2家族成员中，当ATXN 3下调时，促凋亡蛋白BIM和抗促凋亡蛋白Bcl-xl的表达显著增加。BIM的下调保护NB细胞免受哌立福新/MK-2206和ATXN 3下调的组合。ATXN 3的下调没有增加，但降低了NB细胞对依托泊苷/顺铂的敏感性，并且Bcl-xl的敲低减弱了这种敏感性的降低。ATXN 3的下调增强了AKT抑制剂（哌立福新或MK-2206）通过BIM诱导的细胞死亡，但减少了化疗药物（依托泊苷或顺铂）通过Bcl-xl诱导的细胞死亡。ATXN 3的表达可作为选择不同治疗方案的指标。
Chemotherapy 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. The 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. Downregulation 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. Downregulation 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.
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影响因子：
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影响因子：
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影响因子：
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