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Clin Exp Pharmacol Physiol ; 47(9): 1611-1621, 2020 09.
Article in English | MEDLINE | ID: mdl-32415699

ABSTRACT

This study investigated the effect of ellagic acid (EA) on SKOV-3 cell growth and invasiveness and tested if the underlying mechanism involves modulating autophagy. Cells were treated with EA in the presence or absence of chloroquine (CQ), an autophagy inhibitor, compound C (CC), an AMPK inhibitor, or an insulin-like growth factor-1 (IGF-1), a PI3K/Akt activator. EA, at an IC50 of 36.6 µmol/L, inhibited cell proliferation, migration, and invasion and induced cell apoptosis in SKOV-3 cells. These events were prevented by CQ. Also, EA increased levels of Beclin-1, ATG-5, LC3I/II, Bax, cleaved caspase-3/8 and reduced those of p62 and Bcl-2 in these cancer cells. Mechanistically, EA decreased levels of p-S6K1 (Thr389 ) and 4EBP-1 (Thr37/46 ), two downstream targets of mTORC1, and p-Akt (Thr308 ) but increased levels of AMPK (Thr172 ) and p-raptor (Ser792 ), a natural inhibitor of mTORC1. CC or IGF-1 alone partially prevented the effect of EA on cell survival, cell invasions, and levels of LDH, Beclin-1, and cleaved caspase-3. In conclusion, EA can inhibit SKOV-3 growth, migration, and invasion by activating cytotoxic autophagy mediated by inhibition of mTORC1 and Akt and activation of AMPK.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Autophagy/drug effects , Ellagic Acid/pharmacology , Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors , Ovarian Neoplasms/drug therapy , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Apoptosis/drug effects , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Enzyme Activation , Enzyme Activators/pharmacology , Female , Humans , Mechanistic Target of Rapamycin Complex 1/metabolism , Neoplasm Invasiveness , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction
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