Hyperforin inhibits Akt1 kinase activity and promotes caspase-mediated apoptosis involving Bad and Noxa activation in human myeloid tumor cells.
Hyperforin inhibits Akt1 kinase activity and promotes caspase-mediated apoptosis involving Bad and Noxa activation in human myeloid tumor cells.
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DOI：
10.1371/journal.pone.0025963
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Bauvois B
中科院分区：
文献类型：
--
作者：
Merhi F;Tang R;Piedfer M;Mathieu J;Bombarda I;Zaher M;Kolb JP;Billard C;Bauvois B
天然间苯三酚金丝桃素HF显示出抗炎和抗肿瘤的潜在药理作用。急性髓系白血病(AML)细胞异常增殖并逃脱细胞凋亡。在此，我们研究了纯化的HF对AML细胞功能障碍的影响及其机制。HF以时间和浓度依赖的方式抑制AML细胞(U937、OCI-AML3、NB4、HL-60)的生长，诱导细胞凋亡，表现为亚G1期聚集、磷脂酰丝氨酸外化和DNA片段化。HF还可诱导原代AML细胞发生凋亡，而正常血细胞不受影响。U937细胞的凋亡过程伴随着抗凋亡的Bcl2下调、促凋亡的NoxA上调、线粒体膜去极化、原天冬氨酸酶的激活和caspase底物PARP-1的裂解。一般的caspase抑制剂Z-VAD-fmk和caspase-9和caspase-3的特异性抑制剂，而不是caspase-8的抑制剂，可显著抑制细胞的凋亡。HF介导的细胞凋亡与活性Akt1(位于Ser473)和Akt1底物Bad(位于Ser136)的去磷酸化有关，后者激活了Bad促凋亡功能。HF抑制Akt1的激酶活性，与变构Akt1抑制剂Akt-i-合用可显著促进U937细胞的凋亡。我们的数据提供了新的证据，表明HF在AML细胞中的促凋亡作用涉及抑制Akt1信号转导，线粒体和Bcl2成员功能障碍，以及Proaspase-9/-3的激活。HF对线粒体和Akt1通路的联合阻断可能对AML的治疗有意义。
The natural phloroglucinol hyperforin HF displays anti-inflammatory and anti-tumoral properties of potential pharmacological interest. Acute myeloid leukemia (AML) cells abnormally proliferate and escape apoptosis. Herein, the effects and mechanisms of purified HF on AML cell dysfunction were investigated in AML cell lines defining distinct AML subfamilies and primary AML cells cultured ex vivo. HF inhibited in a time- and concentration-dependent manner the growth of AML cell lines (U937, OCI-AML3, NB4, HL-60) by inducing apoptosis as evidenced by accumulation of sub-G1 population, phosphatidylserine externalization and DNA fragmentation. HF also induced apoptosis in primary AML blasts, whereas normal blood cells were not affected. The apoptotic process in U937 cells was accompanied by downregulation of anti-apoptotic Bcl-2, upregulation of pro-apoptotic Noxa, mitochondrial membrane depolarization, activation of procaspases and cleavage of the caspase substrate PARP-1. The general caspase inhibitor Z-VAD-fmk and the caspase-9- and -3-specific inhibitors, but not caspase-8 inhibitor, significantly attenuated apoptosis. HF-mediated apoptosis was associated with dephosphorylation of active Akt1 (at Ser473) and Akt1 substrate Bad (at Ser136) which activates Bad pro-apoptotic function. HF supppressed the kinase activity of Akt1, and combined treatment with the allosteric Akt1 inhibitor Akt-I-VIII significantly enhanced apoptosis of U937 cells. Our data provide new evidence that HF's pro-apoptotic effect in AML cells involved inhibition of Akt1 signaling, mitochondria and Bcl-2 members dysfunctions, and activation of procaspases -9/-3. Combined interruption of mitochondrial and Akt1 pathways by HF may have implications for AML treatment.
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影响因子：
3.7
作者：
Bauvois, B;VanWeyenbergh, J;Wietzerbin, J
通讯作者：
Wietzerbin, J
影响因子：
5
作者：
Dell'Aica, Isabella;Caniato, Rosy;Garbisa, Spiridione
通讯作者：
Garbisa, Spiridione
影响因子：
8
作者：
Feisst, Christian;Pergola, Carlo;Werz, Oliver
通讯作者：
Werz, Oliver
影响因子：
3.8
作者：
Guan, Liying;Huang, Fang;Xu, Caimin
通讯作者：
Xu, Caimin
影响因子：
6.4
作者：
Afanasyeva, Elena A.;Komarova, Elena Yu.;Guzhova, Irina V.
通讯作者：
Guzhova, Irina V.