Novel tamoxifen derivative Ridaifen-B induces Bcl-2 independent autophagy without estrogen receptor involvement.
Novel tamoxifen derivative Ridaifen-B induces Bcl-2 independent autophagy without estrogen receptor involvement.
复制标题
DOI：
10.1016/j.bbrc.2013.05.040
复制
发表时间：
2013-06
影响因子：
3.1
通讯作者：
Y. Nagahara;Midori Takeyoshi;S. Sakemoto;Isamu Shiina;Kenya Nakata;K. Fujimori;Yanwen Wang;Eri Umeda;C. Watanabe;Shoko Uetake;T. Yamori;S. Dan;Yoji Yoshimi;T. Shinomiya;M. Ikekita
中科院分区：
文献类型：
--
作者：
Y. Nagahara;Midori Takeyoshi;S. Sakemoto;Isamu Shiina;Kenya Nakata;K. Fujimori;Yanwen Wang;Eri Umeda;C. Watanabe;Shoko Uetake;T. Yamori;S. Dan;Yoji Yoshimi;T. Shinomiya;M. Ikekita
自噬是真核细胞中的一种自蛋白水解过程，导致细胞内蛋白质和细胞器在自噬体中被隔离。自噬的激活可以促进肿瘤的持续生长，而广泛的自噬会导致细胞死亡。在之前的研究中，我们合成了一种新的他莫昔芬衍生物，Ridaifen (RID)-B。即使在雌激素受体（ER）阴性的细胞中，RID-B也能诱导线粒体参与的细胞凋亡。由于他莫昔芬诱导自噬而非凋亡，我们在本研究中使用RID-B处理er阴性Jurkat细胞。RID-B处理诱导细胞凋亡，LC3和溶酶体共定位，导致自溶酶体的形成。Western blotting显示，RID-B处理后LC3转化为LC3- i到LC3- ii，提示RID-B诱导自噬而不涉及ER。此外，过表达抗凋亡蛋白Bcl-2抑制rid - b诱导的细胞死亡，但不诱导自噬。这些结果推测rid - b诱导的自噬不依赖于Bcl-2，这使得rid - b诱导的自噬不同于rid - b诱导的细胞凋亡。由于在RID-B治疗过程中Beclin1水平不变，因此RID-B诱导的自噬途径是不依赖于Bcl-2/Beclin1的非典型途径。
Autophagy is a self-proteolysis process in eukaryotic cells that results in the sequestering of intracellular proteins and organelles in autophagosomes. Activation of autophagy progress continued growth of some tumors, instead extensive autophagy induces cell death. In a previous study, we synthesized a novel tamoxifen derivative, Ridaifen (RID)-B. RID-B induced mitochondria-involved apoptosis even in estrogen receptor (ER)-negative cells. Since tamoxifen induces autophagy other than apoptosis, we treated ER-negative Jurkat cells with RID-B in the present study. RID-B treatment induced apoptosis and LC3 and lysosome colocalization, which results in the formation of autolysosomes. Western blotting revealed that LC3 was converted to LC3-I to LC3-II with RID-B treatment, suggesting that RID-B induced autophagy without ER involvement. Moreover, overexpression of the anti-apoptotic protein Bcl-2 suppressed the RID-B-induced cell death, but not the induction of autophagy. These results presumed that RID-B-induced autophagy is independent of Bcl-2, making RID-B-induced autophagy different from RID-B-induced apoptosis. Since Beclin 1 level is unchanged during RID-B treatment, RID-B induced autophagy pathway is Bcl-2/Beclin1 independent noncanonical pathway.