RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines
RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines
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DOI：
10.1093/neuonc/nor129
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发表时间：
2011-12-01
期刊：
影响因子：
15.9
通讯作者：
Coyle, Beth
中科院分区：
文献类型：
--
作者：
Levesley, Jane;Lusher, Meryl E.;Coyle, Beth
RASSF1A肿瘤抑制基因可能是迄今为止在髓母细胞瘤中发现的最重要的候选基因，在79%的原发肿瘤中表观遗传学上是沉默的。然而，它的功能作用以前并没有在这种类型的肿瘤中得到解决。在这里，我们证明了RASSF1A的表达促进了髓母细胞瘤细胞在激活外在和内在的凋亡通路后的细胞死亡。稳定表达RASSF1A的UW228-3细胞用抗CD95抗体诱导外源性凋亡，依托泊苷或顺铂激活内源性凋亡，以caspase依赖的方式增强肿瘤细胞杀伤。这导致促凋亡的bcl2家族成员bax的激活增加。在这些知识的基础上，我们展示了如何使用新型的仅BH3模拟ABT-737与化疗药物结合靶向bcl2抗凋亡成员来克服髓母细胞瘤细胞中RASSF1A功能的丧失。我们发现，ABT-737通过增加Bax的激活，增加了对DNA损伤诱导的细胞凋亡的敏感性，而与RASSF1A的表达状态无关。我们的发现确定RASSF1A肿瘤抑制因子是凋亡信号通路的促进者。对其作用机制的研究表明，在其缺失的情况下，这些通路仍然可以被促进，以及这些通路如何潜在地成为髓母细胞瘤的新治疗靶点。
The RASSF1A tumor suppressor is potentially the most important candidate gene identified in medulloblastoma to date, being epigenetically silenced in >79% of primary tumors. However, its functional role has not been previously addressed in this tumor type. Here, we demonstrate that expression of RASSF1A promotes the induction of cell death after activation of both the extrinsic and intrinsic apoptotic pathways in medulloblastoma cells. Treatment of UW228-3 cells stably expressing RASSF1A with an anti-CD95 antibody to induce extrinsic apoptosis and etoposide or cisplatin to activate intrinsic apoptosis augmented tumor cell killing in a caspase-dependent manner. This led to increased activation of the pro-apoptotic BCL-2 family member BAX. On the basis of this knowledge, we demonstrate how the loss of RASSF1A function in medulloblastoma cells might be overcome using the novel BH3-only mimetic ABT-737 in combination with chemotherapeutic agents to target the BCL-2 anti-apoptotic members. We show that ABT-737 increased susceptibility to apoptosis induced by DNA damage regardless of RASSF1A expression status through increased activation of BAX. Our findings identify the RASSF1A tumor suppressor as a promoter of apoptotic signaling pathways. Investigation of its mechanism of action has revealed that these pathways can still be promoted in its absence and how these potentially represent novel therapeutic targets for medulloblastoma.