Bakkenolide A通过调节HDAC3和PI3K / Akt相关的信号通路来抑制白血病。,Biomedicine & Pharmacotherapy

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Bakkenolide A通过调节HDAC3和PI3K / Akt相关的信号通路来抑制白血病。
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2016-10-25 , DOI: 10.1016/j.biopha.2016.07.049
Lei Zhang ₁ , Ze Hong ₂ , Rong-Rong Zhang ₂ , Xing-Zhen Sun ₂ , Yu-Fang Yuan ₂ , Jian Hu ₂ , Xiang Wang ₂

Affiliation

白血病已成为第三种杀死全世界许多人的癌症。有人建议从甜菜粉虱（Petasites tricholobus）中提取的Bakkenolide A（Bak）具有抗癌作用，并对炎症性细胞因子的形成具有保护作用。越来越多的证据表明，组蛋白脱乙酰基酶3（HDAC3）通过细胞死亡，细胞凋亡和炎症在癌症形成和持久性中起着至关重要的作用。但是，尚不清楚Bakkenolide A在调节白血病中的功能，尤其是通过HDAC3。在这里，我们发现与邻近的正常组织相比，白血病临床样品中的HDAC3上调。然后通过RNA干扰在K562细胞中敲低HDAC3的表达。并且抑制HDAC3表达能够改善白血病的侵袭，迁移和增殖。此外，我们还发现HDAC3与IκBα结合，影响随后的炎症反应。此外，发现Bakkenolide A通过PI3K调节的信号传导途径抑制白血病细胞的炎症反应，诱导凋亡和细胞死亡，下调IKKs表达并抑制IL-1β，IL-18和TNF-α的促炎细胞因子。在HDAC3敲减和Bakkenolide A处理的细胞中观察到Caspase3 / 7的上调，诱导白血病细胞凋亡。另外，通过HDAC3-敲低和Bakkenolide A处理激活了Akt和GSK的表达。因此，这些结果表明，白血病细胞中Bakkenolide A介导的HDAC3致敏似乎与PI3K途径的诱导与IKKs，Akt / GSK和胱天蛋白酶的激活有关，从而导致炎症，细胞死亡和细胞凋亡。发现Bakkenolide A可通过PI3K调节的信号通路抑制炎症，诱导白血病细胞凋亡和细胞死亡，下调IKKs表达并抑制IL-1β，IL-18和TNF-α的促炎细胞因子。在HDAC3敲减和Bakkenolide A处理的细胞中观察到Caspase3 / 7的上调，诱导白血病细胞凋亡。另外，通过HDAC3-敲低和Bakkenolide A处理激活了Akt和GSK的表达。因此，这些结果表明，白血病细胞中Bakkenolide A介导的HDAC3致敏似乎与PI3K途径的诱导与IKKs，Akt / GSK和胱天蛋白酶的激活有关，从而导致炎症，细胞死亡和细胞凋亡。发现Bakkenolide A可通过PI3K调节的信号通路抑制炎症，诱导白血病细胞凋亡和细胞死亡，下调IKKs表达并抑制IL-1β，IL-18和TNF-α的促炎细胞因子。在HDAC3敲减和Bakkenolide A处理的细胞中观察到Caspase3 / 7的上调，诱导白血病细胞凋亡。另外，通过HDAC3-敲低和Bakkenolide A处理激活了Akt和GSK的表达。因此，这些结果表明，白血病细胞中Bakkenolide A介导的HDAC3致敏似乎与PI3K途径的诱导与IKKs，Akt / GSK和胱天蛋白酶的激活有关，从而导致炎症，细胞死亡和细胞凋亡。下调IKK的表达并抑制IL-1β，IL-18和TNF-α的促炎细胞因子。在HDAC3敲减和Bakkenolide A处理的细胞中观察到Caspase3 / 7的上调，诱导白血病细胞凋亡。另外，通过HDAC3-敲低和Bakkenolide A处理激活了Akt和GSK的表达。因此，这些结果表明，白血病细胞中Bakkenolide A介导的HDAC3致敏似乎与PI3K途径的诱导与IKKs，Akt / GSK和胱天蛋白酶的激活有关，从而导致炎症，细胞死亡和细胞凋亡。下调IKK的表达并抑制IL-1β，IL-18和TNF-α的促炎细胞因子。在HDAC3敲减和Bakkenolide A处理的细胞中观察到Caspase3 / 7的上调，诱导白血病细胞凋亡。另外，通过HDAC3-敲低和Bakkenolide A处理激活了Akt和GSK的表达。因此，这些结果表明，白血病细胞中Bakkenolide A介导的HDAC3致敏似乎与PI3K途径的诱导与IKKs，Akt / GSK和胱天蛋白酶的激活有关，从而导致炎症，细胞死亡和细胞凋亡。HDAC3基因敲低和Bakkenolide A处理可激活Akt和GSK的表达。因此，这些结果表明，白血病细胞中Bakkenolide A介导的HDAC3致敏似乎与PI3K途径的诱导与IKKs，Akt / GSK和胱天蛋白酶的激活有关，从而导致炎症，细胞死亡和细胞凋亡。HDAC3基因敲低和Bakkenolide A处理可激活Akt和GSK的表达。因此，这些结果表明，白血病细胞中Bakkenolide A介导的HDAC3致敏似乎与PI3K途径的诱导与IKKs，Akt / GSK和胱天蛋白酶的激活有关，从而导致炎症，细胞死亡和细胞凋亡。

"点击查看英文标题和摘要"

Bakkenolide A inhibits leukemia by regulation of HDAC3 and PI3K/Akt-related signaling pathways.

Leukemia has been the third type of cancer killing many people across the world. Bakkenolide A (Bak), extracted from Petasites tricholobus, has been suggested to against cancer and display protective effects on inflammatory cytokines formation. And increasing evidences suggest that histone deacetylase 3 (HDAC3) plays vital roles in cancer formation and persistence via cell death, apoptosis and inflammation. But the function of Bakkenolide A in regulating leukemia is not understood yet, particularly via HDAC3. Here, we found that HDAC3 is up-regulated in clinical samples of leukemia compared with adjacent normal tissues. Then the expression of HDAC3 was knocked down via RNA interference in K562 cells. And inhibition of HDAC3 expression is able to improve leukemia invasion, migration and proliferation. Further, we also found HDAC3 bound to IκBα, affecting subsequent inflammation response. Moreover, Bakkenolide A was found to inhibit inflammation, induce apoptosis and cell death in leukemia cells via PI3K-regulated signaling pathway, down-regulating IKKs expression and suppressing in proinflammatory cytokines of IL-1β, IL-18 and TNF-α. Up-regulation of Caspase3/7 was observed in cells of HDAC3-knockdown and Bakkenolide A treatment, inducing leukemia cell apoptosis. Also, the expression of Akt and GSK were activated by HDAC3-knockdown and Bakkenolide A-treatment. Thus, these results indicated that Bakkenolide A-mediated HDAC3 sensitization in leukemia cells seem to be associated with activation of effector IKKs, Akt/GSK, and caspases through induction of the PI3K pathway, leading to inflammation, cell death, and apoptosis.

更新日期：2019-11-01

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