Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution.
Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution.
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DOI：
10.18632/oncotarget.5013
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发表时间：
2015-10-06
期刊：
影响因子：
--
通讯作者：
Sun X
中科院分区：
文献类型：
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作者：
Xu W;Jing L;Wang Q;Lin CC;Chen X;Diao J;Liu Y;Sun X
内源性细胞凋亡消除了DNA损伤的细胞和癌基因表达异常的细胞。PGAM5是磷酸甘油酸变位酶家族的成员，有两个剪接变异体：PGAM5L(长形式)和PGAM5S(短形式)。已有研究表明，PGAM5处于多种坏死途径的交汇点。然而，PGAM5在内源性细胞凋亡中的作用仍存在争议。在此，我们报道了在华蟾素和星形孢子素诱导的内源性细胞凋亡中，激活Bax和去磷酸化Drp1的先决条件是PGAM5L，而不是PGAM5S。敲除PGAM5L可抑制Bax向线粒体的转位，并减少线粒体的分裂。在华蟾素和星形孢子素处理的HCT116细胞中均观察到PGAM5L与DRP1的相互作用，而在HCT116Bax−/−细胞中未观察到这种相互作用。BAX基因转导挽救了华蟾素和星形孢子素刺激的HCT116BAX−/−细胞中三联体的形成。与顺铂相比，Arenobufagin在正交性和异质性结直肠癌模型中均显示出显著的抗癌作用，且毒性作用较小。Bax-PGAM5L-Drp1复合体在体外用华蟾素和星形孢子素处理的大肠癌细胞中检测到，在体内用华蟾素和顺铂处理的肿瘤中也检测到。综上所述，我们的结果表明Bax-PGAM5L-Drp1复合体是内在细胞凋亡执行所必需的。
Intrinsic apoptosis eliminates cells with damaged DNA and cells with dysregulated expression of oncogene. PGAM5, a member of the phosphoglycerate mutase family, has two splicing variants: PGAM5L (the long form) and PGAM5S (the short form). It has been well established that PGAM5 is at the convergent point of multiple necrosis pathways. However, the role of PGAM5 in intrinsic apoptosis is still controversial. Here we report that the PGAM5L, but not PGAM5S is a prerequisite for the activation of Bax and dephosphorylation of Drp1 in arenobufagin and staurosporine induced intrinsic apoptosis. Knockdown of PGAM5L inhibits the translocation of Bax to the mitochondria and reduces mitochondrial fission. The interaction between PGAM5L and Drp1 was observed in both arenobufagin and staurosporine treated HCT116 cells, but not in HCT116 Bax−/− cells. Bax transfection rescues the formation of the triplex in both arenobufagin and staurosporine stimulated HCT116 Bax−/− cells. Arenobufagin shows remarkable anti-cancer effects both in orthotropic and heterotropic CRC models and demonstrates less toxic effects as compared with that of cisplatin. Bax-PGAM5L-Drp1 complex is detected in arenobufagin and staurosporine treated CRC cells in vitro and in arenobufagin and cisplatin treated tumor in vivo as well. In summary, our results demonstrate that Bax-PGAM5L-Drp1 complex is required for intrinsic apoptosis execution.