title: Epigallocatechin gallate sensitizes cisplatin-resistant oral cancer CAR cell apoptosis and autophagy through stimulating AKT/STAT3 pathway and suppressing multidrug resistance 1 signaling.
abstract: Epigallocatechin gallate (EGCG) is a green tea polyphenol that presents anticancer activities in multiple cancer cells, but no available report was addressed for the underling molecular mechanism of cytotoxic impacts on drug-resistant oral squamous cell carcinoma cells. In the present study, the inhibitory effects of EGCG were experienced on cisplatin-resistant oral cancer CAR cells. EGCG inhibited cell viability in a time- and concentration-dependent manner by a sulforhodamine B (SRB) assay. EGCG induced CAR cell apoptosis and autophagy by 4',6-diamidino-2-phenylindole (DAPI) dye, acridine orange (AO) staining and green fluorescent protein (GFP)-tagged LC3B assay, respectively. EGCG also significantly enhanced caspase-9 and caspase-3 activities by caspase activity assay. EGCG markedly increased the protein levels of Bax, cleaved caspase-9, cleaved caspase-3, Atg5, Atg7, Atg12, Beclin-1, and LC3B-II, as well as significantly decreased the expression of Bcl-2, phosphorylated AKT (Ser473) and phosphorylation of STAT3 on Tyr705 by western blotting in CAR cells. Importantly, the protein and gene expression of multidrug resistance 1 (MDR1) were dose-dependently inhibited by EGCG. Overall, downregulation of MDR1 levels and alterations of AKT/STAT3 signaling contributed to EGCG-induced apoptosis and autophagy in CAR cells. Based on these results, EGCG has the potential for therapeutic effect on oral cancer and may be useful for long-term oral cancer prevention in the future. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 845-855, 2017.
authors.affiliation: Department of Otolaryngology, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan.|Department of Otorhinolaryngology Head and Neck Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Chien-Han
authors.initials: CH
authors.lastname: Yuan
authors.affiliation: Kaohsiung Armed Forces General Hospital, Medical Education Center, Kaohsiung, Taiwan.|Institute of Biochemistry and Biotechnology, Chung Shan Medical University and Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Chi-Ting
authors.initials: CT
authors.lastname: Horng
authors.affiliation: Kaohsiung Veterans General Hospital Pingtung Branch, Pingtung, Taiwan.
authors.forename: Chiu-Fang
authors.initials: CF
authors.lastname: Lee
authors.affiliation: Kaohsiung Veterans General Hospital Pingtung Branch, Pingtung, Taiwan.
authors.forename: Ni-Na
authors.initials: NN
authors.lastname: Chiang
authors.affiliation: Human Genetic Center, China Medical University Hospital, Taichung, Taiwan.|School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Fuu-Jen
authors.initials: FJ
authors.lastname: Tsai
authors.affiliation: School of Nutrition and Health Sciences, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Cheng
authors.initials: CC
authors.lastname: Lu
authors.affiliation: Department of Nursing, Chung-Jen Junior College of Nursing, Health Sciences and Management, Chiayi County, Taiwan.
authors.forename: Jo-Hua
authors.initials: JH
authors.lastname: Chiang
authors.affiliation: Department of Biological Science and Technology, China Medical University, Taichung, Taiwan.
authors.forename: Yuan-Man
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Jai-Sing
authors.initials: JS
authors.lastname: Yang
authors.affiliation: Department of Pharmacy and Master Program, Tajen University, Pingtung, Taiwan.
authors.forename: Fu-An
authors.initials: FA
authors.lastname: Chen
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects*; D000071183:Autophagy-Related Proteins / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D008856:Microscopy, Fluorescence; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D051017:Apoptosis Regulatory Proteins; D000071183:Autophagy-Related Proteins; D050796:STAT3 Transcription Factor; D002392:Catechin; C045651:epigallocatechin gallate; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D053453:Caspase 9; D002945:Cisplatin
keywords: AKT/STAT3 signaling; MDR1; apoptosis; autophagy; epigallocatechin gallate