Grape seed extract targets mitochondrial electron transport chain complex III and induces oxidative and metabolic stress leading to cytoprotective autophagy and apoptotic death in human head and neck cancer cells

摘要: Head and neck squamous cell carcinoma (HNSCC) is a major killer worldwide innovative measures are urgently warranted to lower the morbidity mortality caused by this malignancy. Aberrant redox metabolic status in HNSCC cells offer unique opportunity specifically target cancer cells. Therefore, we investigated efficacy of grape seed extract (GSE) bioenergetic alterations GSE treatment decreased mitochondrial electron transport chain complex III activity, increased superoxide levels depleted cellular antioxidant (glutathione), thus resulting loss membrane potential human Detroit 562 FaDu Polyethylene glycol-SOD addition reversed GSE-mediated apoptosis without restoring activity. Along with changes, inhibited extracellular acidification rate (representing glycolysis) oxygen consumption (indicating oxidative phosphorylation) leading stress Molecular studies revealed that activated AMP-activated protein kinase (AMPK), suppressed Akt/mTOR/4E-BP1/S6K signaling both Interestingly, autophagic load cells, autophagy inhibition significantly augmented these Consistent vitro results, vivo analyses also showed feeding nude mice AMPK induced-autophagy xenograft tumor tissues. Overall, findings as for first time targets ETC induces stress, thereby, causing apoptotic death