Mitochondrial apoptosis is induced by Alkoxy phenyl-1-propanone derivatives through PP2A-mediated dephosphorylation of Bad and Foxo3A in CLL
Mitochondrial apoptosis is induced by Alkoxy phenyl-1-propanone derivatives through PP2A-mediated dephosphorylation of Bad and Foxo3A in CLL
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DOI：
10.1038/s41375-018-0288-5
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发表时间：
2019-05-01
期刊：
影响因子：
11.4
通讯作者：
Brunati, Anna Maria
中科院分区：
文献类型：
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作者：
Pagano, Mario Angelo;Tibaldi, Elena;Brunati, Anna Maria
蛋白磷酸酶2 A(PP2A)是一种肿瘤抑制因子，其强烈的抑制作用是慢性淋巴细胞白血病(CLL)磷酸化依赖、抗凋亡机制的基础。PP2A的失活是由于其催化亚基Y307的磷酸化与其在CLL中高表达的蛋白抑制物集的相互作用和Src家族蛋白激酶Lyn异常胞液池的协同作用所致。在本研究中，我们开发了一个化合物文库，其中最有效的是名为cc11的化合物，它通过破坏PP2A/SET复合体来恢复PP2A的活性，从而触发线粒体的凋亡途径。这一过程涉及到只有BH3-Only的促凋亡蛋白Bad和Bim被募集到线粒体，前者在直接去磷酸化时重新表达，后者在其转录因子FOXO3a去磷酸化和激活时新表达。这些发现突显了PP2A拮抗Akt控制的生存通路，Akt使磷酸化，从而抑制包括Bad和FOXO3a在内的各种促凋亡因子和肿瘤抑制因子。此外，通过降低Lyn的活性，CC11的PP2A介导的促凋亡作用被协同增强。我们的结果表明，CC11是一种很有前景的先导化合物，旨在消除CLL中异常的致癌信号，为新的治疗理论奠定了基础。
Protein phosphatase 2 A (PP2A) is a tumour suppressor whose strong inhibition underlies the phosphorylation-dependent, anti-apoptotic mechanisms in Chronic Lymphocytic Leukemia (CLL). Inactivation of PP2A is due to the cooperative action of the phosphorylation of Y307 of its catalytic subunit by the aberrant cytosolic pool of the Src Family Kinase Lyn and the interaction with its protein inhibitor SET, which is overexpressed in CLL. In this study, we developed a library of compounds, the most potent being the one named CC11, which restores PP2A activity by disrupting the PP2A/SET complex, thereby triggering the mitochondrial pathway of apoptosis. This process involves the recruitment of the pro-apoptotic BH3-only proteins Bad and Bim to mitochondria, the former upon direct dephosphorylation and the latter being newly expressed upon dephosphorylation and activation of its transcription factor FoxO3a. These findings highlight that PP2A antagonizes the prosurvival pathways controlled by Akt, which phosphorylates and thereby suppresses a variety of pro-apoptotic factors and tumour suppressors including Bad and FoxO3a. Furthermore, the PP2A-mediated pro-apoptotic effect of CC11 is synergistically potentiated by the abrogation of Lyn's activity. Our results show that CC11 represents a promising lead compound for a new therapeutic rationale aimed at abrogating the aberrant oncogenic signals in CLL.