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

Abstract	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.
Authors	Chao-Hsiang Chang, Chao-Ying Lee, Chi-Cheng Lu, Fuu-Jen Tsai, Yuan-Man Hsu, Je-Wei Tsao, Yu-Ning Juan, Hong-Yi Chiu, Jai-Sing Yang, Ching-Chiung Wang
Journal	International journal of oncology (Int J Oncol) Vol. 50 Issue 3 Pg. 873-882 (Mar 2017) ISSN: 1791-2423 [Electronic] Greece
PMID	28197628 (Publication Type: Journal Article)
Chemical References	ATG12 protein, human ATG5 protein, human Amino Acid Chloromethyl Ketones Antineoplastic Agents Antineoplastic Agents, Phytogenic Autophagy-Related Protein 12 Autophagy-Related Protein 5 Beclin-1 MAP1LC3A protein, human Microtubule-Associated Proteins RNA, Messenger Stilbenes benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone MTOR protein, human Proto-Oncogene Proteins c-akt TOR Serine-Threonine Kinases AMP-Activated Protein Kinases Caspase 3 Caspase 9 Cisplatin Resveratrol
Topics	AMP-Activated Protein Kinases (metabolism) Amino Acid Chloromethyl Ketones (pharmacology) Antineoplastic Agents (pharmacology) Antineoplastic Agents, Phytogenic (pharmacology) Apoptosis (drug effects) Autophagy (drug effects) Autophagy-Related Protein 12 (genetics) Autophagy-Related Protein 5 (genetics) Beclin-1 (genetics) Caspase 3 (metabolism) Caspase 9 (metabolism) Cell Line, Tumor Cisplatin (pharmacology) DNA Fragmentation (drug effects) Drug Resistance, Neoplasm Humans Microtubule-Associated Proteins (genetics) Mouth Neoplasms (pathology) Phosphorylation (drug effects) Proto-Oncogene Proteins c-akt (metabolism) RNA, Messenger (genetics) Resveratrol Signal Transduction (drug effects) Stilbenes (pharmacology) TOR Serine-Threonine Kinases (metabolism)

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