The Bcl-2 Homology Domain 3 Mimetic Gossypol Induces Both Beclin 1-dependent and Beclin 1-independent Cytoprotective Autophagy in Cancer Cells
The Bcl-2 Homology Domain 3 Mimetic Gossypol Induces Both Beclin 1-dependent and Beclin 1-independent Cytoprotective Autophagy in Cancer Cells
复制标题
Bcl-2 同源结构域 3 模拟棉酚在癌细胞中诱导 Beclin 1 依赖性和 Beclin 1 独立的细胞保护性自噬
DOI：
10.1074/jbc.m110.118125
复制
发表时间：
2010-08-13
影响因子：
4.8
通讯作者：
Mehrpour, Maryam
中科院分区：
文献类型：
--
作者：
Gao, Ping;Bauvy, Chantal;Mehrpour, Maryam
棉酚是从棉籽中分离的天然Bcl-2同源结构域3模拟化合物，目前正在临床试验中进行评估。在这里，我们提供的证据表明，棉酚诱导自噬，然后在MCF-7人乳腺癌和HeLa细胞系的凋亡细胞死亡。我们首先表明，敲低Bcl-2同源结构域3-唯一的蛋白Beclin 1减少棉酚诱导的自噬MCF-7细胞，但不是在HeLa细胞。棉酚抑制Beclin 1和Bcl-2（B细胞白血病/淋巴瘤2）之间的相互作用，拮抗Bcl-2对自噬的抑制，从而刺激自噬。然后，我们表明，敲低Vps 34减少棉酚诱导的自噬在两个细胞系，并与此一致，磷脂酰肌醇3-磷酸结合蛋白WIPI-1被招募到自噬体膜。此外，Atg 5敲除还减少棉酚介导的自噬。我们的结论是棉酚诱导自噬的一个典型和非典型的方式。值得注意的是，我们发现，棉酚介导的凋亡细胞死亡是加强治疗与自噬抑制剂渥曼青霉素或小干扰RNA对必需的自噬基因（Vps 34，Beclin 1，和Atg 5）。我们的研究结果支持棉酚诱导的自噬是细胞保护性的，而不是这种化合物诱导的细胞死亡过程的一部分。
Gossypol, a natural Bcl-2 homology domain 3 mimetic compound isolated from cottonseeds, is currently being evaluated in clinical trials. Here, we provide evidence that gossypol induces autophagy followed by apoptotic cell death in both the MCF-7 human breast adenocarcinoma and HeLa cell lines. We first show that knockdown of the Bcl-2 homology domain 3-only protein Beclin 1 reduces gossypol-induced autophagy in MCF-7 cells, but not in HeLa cells. Gossypol inhibits the interaction between Beclin 1 and Bcl-2 (B-cell leukemia/lymphoma 2), antagonizes the inhibition of autophagy by Bcl-2, and hence stimulates autophagy. We then show that knockdown of Vps34 reduces gossypol-induced autophagy in both cell lines, and consistent with this, the phosphatidylinositol 3-phosphate-binding protein WIPI-1 is recruited to autophagosomal membranes. Further, Atg5 knockdown also reduces gossypol-mediated autophagy. We conclude that gossypol induces autophagy in both a canonical and a noncanonical manner. Notably, we found that gossypol-mediated apoptotic cell death was potentiated by treatment with the autophagy inhibitor wortmannin or with small interfering RNA against essential autophagy genes (Vps34, Beclin 1, and Atg5). Our findings support the notion that gossypol-induced autophagy is cytoprotective and not part of the cell death process induced by this compound.