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 TransductionABSTRACT
Fungal keratitis is an important infection of the eye that may cause devastating effects. Keratitis caused by fungi has been described in many parts of the world mainly in tropical countries. The objective of this study is to report a serious eye infection in an adult with a known history of diabetes caused by an uncommon yeast fungus with details of clinical findings and laboratory investigations. Left eye visual acuity was no perception of light due to end stage neovascular glaucoma. The patient was pseudophakic in both eyes. Culture of a corneal scraping showed yeast like organism on Sabouraud dextrose agar. Gjaerumia minor, a rare yeast but with history of a pulmonary infection in the region, was confirmed with 98% similarity in the large subunit ribosomal RNA gene (accession KY690175). Topical Amphotericin B and oral fluconazole were initiated. The patient showed gradual improvement, epithelial defect healed, infiltration steadily regressed and hypopyon disappeared. We report the first case of fungal keratitis caused by G. minor in Saudi Arabia. Fungal Keratitis should be considered in cases where clinical response to the conventional antibacterial antibiotic treatment is not optimal.
