title: 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.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan, R.O.C.
authors.forename: Chao-Hsiang
authors.initials: CH
authors.lastname: Chang
authors.affiliation: School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Chao-Ying
authors.initials: CY
authors.lastname: Lee
authors.affiliation: Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung 404, Taiwan, R.O.C.
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Yuan-Man
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Je-Wei
authors.initials: JW
authors.lastname: Tsao
authors.affiliation: Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Juan
authors.affiliation: Department of Pharmacy, Buddhist Tzu Chi General Hospital, Hualien 970, Taiwan, R.O.C.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Chiu
authors.affiliation: Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan, R.O.C.
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.affiliation: School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan, R.O.C.
authors.forename: Ching-Chiung
authors.initials: CC
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071192:Autophagy-Related Protein 12 / Q000235:genetics; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D000071186:Beclin-1 / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009062:Mouth Neoplasms / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D013267:Stilbenes / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C466624:ATG12 protein, human; C502778:ATG5 protein, human; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D013267:Stilbenes; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D053148:Caspase 3; D053453:Caspase 9; D002945:Cisplatin; D000077185:Resveratrol