Apoptosis induction of human leukemia cells by Streptomyces sp SY-103 metabolites through activation of caspase-3 and inactivation of Akt
Apoptosis induction of human leukemia cells by Streptomyces sp SY-103 metabolites through activation of caspase-3 and inactivation of Akt
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DOI：
10.3892/ijmm_00000310
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发表时间：
2010-01-01
影响因子：
5.4
通讯作者：
Choi, Yung Hyun
中科院分区：
文献类型：
--
作者：
Jeong, Seong-Yun;Han, Min Ho;Choi, Yung Hyun
从海水样品中分离出23种海洋放线菌。其中，菌株SY-103对人白血病细胞系的细胞毒活性最强。生化试验和16S rDNA测序结果表明，SY-103为链霉菌属菌株。本研究采用反相高效液相色谱法纯化了链霉菌SY-103代谢产物中的细胞毒化合物（PCC），并对PCC诱导培养的人白血病细胞株凋亡的生化机制进行了研究。PCC对细胞产生生长抑制和诱导凋亡的作用，其机制与caspase-3蛋白水解激活和抗凋亡Bcl-2蛋白下调有关。然而，pcc诱导的caspase-3激活和凋亡在Bcl-2过表达的U937细胞中明显减弱。caspase-3特异性抑制剂z-DEVD-fmk可以阻断caspase-3的激活，提高pcc处理的U937细胞的存活率。Akt活性在pcc处理的细胞中也被抑制，磷脂酰肌醇3-激酶(PI3K)/Akt抑制剂LY294002使细胞对pcc诱导的凋亡敏感，表明Akt信号通路的下调在pcc诱导的凋亡中起关键作用。我们的研究结果表明，Bcl-2和PI3K/Akt的一些生物学功能归因于它们抑制pcc诱导的细胞凋亡的能力；因此，提示该化合物是一种有前景的白血病细胞抗癌药物。
We isolated 23 marine actinomycetes from seawater samples. Of these, strain SY-103 exhibited the strongest cytotoxic activity on human leukemic cell lines. Biochemical tests and 16S rDNA sequencing of this strain allowed us to identify SY-103 as a strain of the genus Streptomyces. In the present study, the pure cytotoxic compound (PCC) from Streptomyces sp. SY-103 metabolites was purified by reverse-phase HPLC and the biochemical mechanisms of PCC-induced apoptosis in cultured human leukemic cell lines were investigated. The exposure of cells to PCC resulted in growth inhibition and induction of apoptosis, which was associated with the proteolytic activation of caspase-3 and down-regulation of anti-apoptotic Bcl-2 protein. However, PCC-induced caspase-3 activation and apoptosis were significantly attenuated in Bcl-2 overexpressing U937 cells. z-DEVD-fmk, a caspase-3 specific inhibitor, blocked caspase-3 activation and increased the survival rate of PCC-treated U937 cells. The activity of Akt was also inhibited in PCC-treated cells, and phosphatidylinositol 3-kinase (PI3K)/Akt inhibitor, LY294002, sensitized the cells to PCC-induced apoptosis indicating that the down-regulation of the Akt signaling pathway plays a key role in PCC-induced apoptosis. Our findings imply that some of the biological functions of Bcl-2 and PI3K/Akt are attributed to their ability to inhibit PCC-induced apoptosis; therefore, it is suggested that this compound is a promising anti-cancer agent for leukemia cells.