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Penta-galloyl-glucose induces autophagy and caspase-independent programmed deaths in human PC-3 and mouse TRAMP-C2 prostate cancer cells

机译：Penta-galloyl-glucose在人PC-3和小鼠流浪-C2前列腺癌细胞中诱导自噬和患者无关的程序死亡

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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.

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