Gossypol inhibits phosphorylation of Bcl-2 in human leukemia HL-60 cells
Gossypol inhibits phosphorylation of Bcl-2 in human leukemia HL-60 cells
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DOI：
10.1016/j.ejphar.2010.06.070
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发表时间：
2010-10-25
影响因子：
5
通讯作者：
Jiang, Jikai
中科院分区：
文献类型：
--
作者：
Huang, Li-heng;Hu, Jia-qi;Jiang, Jikai
棉酚是一种有吸引力的治疗性抗肿瘤药物，作为细胞凋亡诱导剂，目前正在临床前测试中进行评估。然而，棉酚诱导恶性细胞凋亡的分子机制尚未完全阐明。在这里，我们研究了棉酚诱导的人白血病 HL-60 细胞凋亡中 Bcl-2/Bcl-xL/Mcl-1 蛋白水平和 Bcl-2 磷酸化的变化。我们发现棉酚处理抑制 HL-60 细胞的生长并诱导细胞凋亡。 Bcl-2/Bcl-xL/Mcl-1 蛋白水平略有降低，并且 Bcl-2 在苏氨酸 56（磷酸化 T56）处的磷酸化没有改变。然而，在暴露于棉酚的细胞中，Bcl-2 丝氨酸 70（磷酸化 S70）的磷酸化显着下调。人们发现这种减少不仅与剂量和时间有关，而且还可以被佛波醇 12,13-二丁酸酯 (PDBu)（一种蛋白激酶 C (PKC) 激活剂）所消除。此外，PDBu 预处理部分阻止了棉酚诱导的 HL-60 细胞凋亡。总的来说，棉酚治疗可以减少白血病 HL-60 细胞中 Bcl-2 在丝氨酸 70 处的磷酸化，并且棉酚可能是白血病患者的有前途的治疗候选者，特别是在 Ser70 处表达磷酸化 Bcl-2 的患者。 (C) 2010 Elsevier B.V. 保留所有权利。
Gossypol is an attractive therapeutic anti-tumor agent as an apoptosis inducer and is being evaluated in preclinical tests. However, the molecular mechanisms underlying apoptosis induction by gossypol in malignant cells have not been completely enunciated. Here we investigate the alterations of Bcl-2/Bcl-xL/Mcl-1 protein levels and Bcl-2 phosphorylation in gossypol-induced apoptosis in human leukemia HL-60 cells. We found that gossypol treatment inhibited cell growth and induced apoptosis in HL-60 cells. Bcl-2/Bcl-xL/Mcl-1 protein levels were slightly reduced and phosphorylation of Bcl-2 at threonine 56 (phospho T56) was not altered. However, phosphorylation of Bcl-2 at serine 70 (phospho S70) was strikingly down-regulated in gossypol-exposed cells. This reduction was found to be not only in both dose- and time-dependent fashion but also obviated by phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC). In addition, pre-treatment of PDBu partially prevented gossypol-induced apoptosis in HL-60 cells. Collectively, gossypol treatment can reduce phosphorylation of Bcl-2 at serine 70 in leukemia HL-60 cells and gossypol may be a promising therapeutical candidate for leukemia patients especially expressing phosphorylated Bcl-2 at Ser70. (C) 2010 Elsevier B.V. All rights reserved.