Pentagalloylglucose induces autophagy and caspase-independent programmed deaths in human PC-3 and mouse TRAMP-C2 prostate cancer cells.
Pentagalloylglucose induces autophagy and caspase-independent programmed deaths in human PC-3 and mouse TRAMP-C2 prostate cancer cells.
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DOI：
10.1158/1535-7163.mct-09-0288
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发表时间：
2009-10
影响因子：
5.7
通讯作者：
Lü J
中科院分区：
文献类型：
--
作者：
Hu H;Chai Y;Wang L;Zhang J;Lee HJ;Kim SH;Lü J
五- o -没食子酰-β- d -葡萄糖（PGG）在裸鼠体内抑制人DU145和PC-3前列腺癌（PCa）异种移植物的生长，提示作为PCa化疗或化学预防剂的潜在效用。我们早期的工作表明caspase介导的DU145和LNCaP PCa细胞凋亡是抗癌活性的一种机制。在侵袭性更强的PC-3 PCa细胞系中，PGG诱导的程序性细胞死亡（PCD）缺乏典型的caspase介导的凋亡形态学和生化变化。相比之下，PGG诱导的自噬特征明显，包括自噬体的形成和PGG暴露48 h后LC-3的脂质修饰。在小鼠trump - c2细胞中也观察到自噬反应。Caspase抑制加重了pgg诱导的总体死亡。在分子变化方面，我们观察到PGG在PC-3和TRAMP C2细胞中快速抑制mTOR下游靶点S6K和4EBP1的磷酸化，但对mTOR本身没有抑制作用，同时AKT磷酸化增加。尽管抑制PI3K增加了pgg诱导的细胞凋亡和自噬，但使用自噬的药物诱导剂或抑制剂或通过敲低自噬介质Beclin-1的实验表明，自噬提供了抑制caspase介导的细胞凋亡的生存信号。敲低RIP-1激酶会增加总体死亡，但不会改变LC-3 II或caspase的激活，因此不支持rip1坏死坏死诱导pg诱导自噬或其他PCD。此外，pgg处理的PC-3细胞丧失了克隆生成能力。PGG在侵袭性PCa细胞系中诱导caspase非依赖性PCD，支持测试其作为治疗caspase耐药复发性PCa的潜在候选药物的优点。
Penta-O-galloyl-β-D-glucose (PGG) suppresses the in vivo growth of human DU145 and PC-3 prostate cancer (PCa) xenografts in nude mice, suggesting potential utility as a PCa chemotherapeutic or chemopreventive agent. Our earlier work implicates caspase-mediated apoptosis in DU145 and LNCaP PCa cells as one mechanism for the anti-cancer activity. We show here that in the more aggressive PC-3 PCa cell line, PGG induced programmed cell deaths (PCD) lacking the typical caspase-mediated apoptotic morphology and biochemical changes. In contrast, PGG induced patent features of autophagy, including formation of autophagosomes and lipid modification of LC-3 after 48 h of PGG exposure. The autophagic responses were also observed in the murine TRAMP-C2 cells. Caspase inhibition exacerbated PGG-induced overall death. As for molecular changes, we observed a rapid inhibition of the phosphorylation of mTOR-downstream targets S6K and 4EBP1 by PGG in PC-3 and TRAMP C2 cells, but not that of mTOR itself, along with increased AKT phosphorylation. Whereas inhibition of PI3K increased both PGG-induced apoptosis and autophagy, experiments with pharmacologic inducer or inhibitor of autophagy or by knocking down autophagy mediator Beclin-1 showed that autophagy provided survival signaling that suppressed caspase-mediated apoptosis. Knocking down of RIP-1 kinase increased overall death, without changing LC-3 II or caspase activation, thus not supporting RIP1-necroptosis for PGG-induction of autophagy or other PCD. Furthermore, PGG-treated PC-3 cells lost clonogenic ability. The induction by PGG of caspase-independent PCD in aggressive PCa cell lines supports testing its merit as a potential drug candidate for therapy of caspase-resistant recurrent PCa.