Pentagalloylglucose induces autophagy and caspase-independent programmed deaths in human PC-3 and mouse TRAMP-C2 prostate cancer cells.

Abstract

Penta-1,2,3,4,6-O-galloyl-beta-d-glucose (PGG) suppresses the in vivo growth of human DU145 and PC-3 prostate cancer xenografts in nude mice, suggesting potential utility as a prostate cancer chemotherapeutic or chemopreventive agent. Our earlier work implicates caspase-mediated apoptosis in DU145 and LNCaP prostate cancer cells as one mechanism for the anticancer activity. We show here that, in the more aggressive PC-3 prostate cancer cell line, PGG induced programmed cell deaths 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 light chain 3 after 48 hours 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 mammalian target of rapamycin-downstream targets S6K and 4EBP1 by PGG in PC-3 and TRAMP-C2 cells but not that of mammalian target of rapamycin itself, along with increased AKT phosphorylation. Whereas the inhibition of phosphatidylinositol 3-kinase increased 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 death receptor-interacting protein 1 kinase increased overall death without changing light chain 3-II or caspase activation, thus not supporting death receptor-interacting protein 1-necroptosis for PGG-induction of autophagy or other programmed cell death. Furthermore, PGG-treated PC-3 cells lost clonogenic ability. The induction by PGG of caspase-independent programmed cell death in aggressive prostate cancer cell lines supports testing its merit as a potential drug candidate for therapy of caspase-resistant recurrent prostate cancer.

• Authors: Hongbo Hu, Yubo Chai, Lei Wang, Jinhui Zhang, Hyo Jeong Lee, Sung-Hoon Kim, Junxuan Lü
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 10 Pg. 2833-43 (Oct 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19825802 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• GTPase-Activating Proteins
• Hydrolyzable Tannins
• Membrane Proteins
• Reactive Oxygen Species
• pentagalloylglucose
• 3-methyladenine
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Caspases
• Adenine
• Sirolimus

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (drug effects)
• Beclin-1
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Screening Assays, Antitumor
• Enzyme Activation (drug effects)
• GTPase-Activating Proteins (metabolism)
• Gene Knockdown Techniques
• Humans
• Hydrolyzable Tannins (pharmacology)
• Male
• Membrane Proteins (metabolism)
• Mice
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostatic Neoplasms (enzymology, pathology)
• Protein Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases
• Tumor Stem Cell Assay