Resveratrol-induced autophagy and apoptosis in cisplatin-resistant human oral cancer CAR cells: A key role of AMPK and Akt/mTOR signaling

• Published in: International journal of oncology Vol. 50; no. 3; pp. 873 - 882
• Main Authors: Chang, Chao-Hsiang, Lee, Chao-Ying, Lu, Chi-Cheng, Tsai, Fuu-Jen, Hsu, Yuan-Man, Tsao, Je-Wei, Juan, Yu-Ning, Chiu, Hong-Yi, Yang, Jai-Sing, Wang, Ching-Chiung
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01.03.2017; Spandidos Publications UK Ltd
• Subjects: Amino Acid Chloromethyl Ketones - pharmacology; AMP-Activated Protein Kinases - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Autophagy-Related Protein 12 - genetics; Autophagy-Related Protein 5 - genetics; Beclin-1 - genetics; Cancer therapies; Care and treatment; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell Line, Tumor; Cellular signal transduction; Chemotherapy; Cisplatin - pharmacology; Cytochrome; Cytoplasm; Deoxyribonucleic acid; Development and progression; DNA; DNA Fragmentation - drug effects; Drug Resistance, Neoplasm; Health aspects; Humans; Immunoglobulins; Kinases; Microtubule-Associated Proteins - genetics; Mitochondria; Morphology; Mouth cancer; Mouth Neoplasms - pathology; Oral cancer; Penicillin; Phosphorylation - drug effects; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Resveratrol; RNA, Messenger - genetics; Rodents; Signal Transduction - drug effects; Stilbenes - pharmacology; TOR Serine-Threonine Kinases - metabolism; United States > US
• DOI: 10.3892/ijo.2017.3866
• ISSN: 1019-6439

Resveratrol is known to be an effective chemo-preventive phytochemical against multiple tumor cells. However, the increasing drug resistance avoids the cancer treatment in oral cavity cancer. In this study, we investigated the oral antitumor activity of resveratrol and its mechanism in cisplatin-resistant human oral cancer CAR cells. Our results demonstrated that resveratrol had an extremely low toxicity in normal oral cells and provoked autophagic cell death to form acidic vesicular organelles (AVOs) and autophagic vacuoles in CAR cells by acridine orange (AO) and monodansylcadaverine (MDC) staining. Either DNA fragmentation or DNA condensation occurred in resveratrol-triggered CAR cell apoptosis. These inhibitors of PI3K class III (3-MA) and AMP-activated protein kinase (AMPK) (compound c) suppressed the autophagic vesicle formation, LC3-II protein levels and autophagy induced by resveratrol. The pan-caspase inhibitor Z-VAD-FMK attenuated resveratrol-triggered cleaved caspase-9, cleaved caspase-3 and cell apoptosis. Resveratrol also enhanced phosphorylation of AMPK and regulated autophagy- and pro-apoptosis-related signals in resveratrol-treated CAR cells. Importantly, resveratrol also stimulated the autophagic mRNA gene expression, including Atg5, Atg12, Beclin-1 and LC3-II in CAR cells. Overall, our findings indicate that resveratrol is likely to induce autophagic and apoptotic death in drug-resistant oral cancer cells and might become a new approach for oral cancer treatment in the near future.