title: Involvement of autophagy induction in penta-1,2,3,4,6-O-galloyl-β-D-glucose-induced senescence-like growth arrest in human cancer cells.
abstract: Growing evidence has demonstrated that autophagy plays important and paradoxical roles in carcinogenesis, while senescence is considered to be a crucial tumor-suppressor mechanism in cancer prevention and treatment. In the present study we demonstrated that both autophagy and senescence were induced in response to penta-1,2,3,4,6-O-galloyl-β-D-glucose (PGG), a chemopreventive polyphonolic compound, in multiple types of cancer cells. Analysis of these 2 events over the experimental time course indicated that autophagy and senescence occurred in parallel early in the process and dissociated later. The long-term culture study suggested that a subpopulation of senescent cells may have the capacity to reenter the cell cycle. Inhibition of autophagy by either a chemical inhibitor or RNA interference led to a significant reduction of PGG-induced senescence, followed by induction of apoptosis. These results suggested that autophagy promoted senescence induction by PGG and that PGG might exert its anticancer activity through autophagy-mediated senescence. For the first time, these findings uncovered the relationships among autophagy, senescence, and apoptosis induced by PGG. In addition, we identified that unfolded protein response signaling played a pivotal role in the autophagy-mediated senescence phenotype. Furthermore, our data showed that activation of MAPK8/9/10 (mitogen-activated protein kinase 8/9/10/c-Jun N-terminal kinases) was an essential upstream signal for PGG-induced autophagy. Finally, the key in vitro results were validated in vivo in a xenograft mouse model of human HepG2 liver cancer. Our findings provided novel insights into understanding the mechanisms and functions of PGG-induced autophagy and senescence in human cancer cells.
authors.affiliation: Department of Nutrition and Health; College of Food Science and Nutritional Engineering; Beijing Key Laboratory of Functional Food from Plant Resources; China Agricultural University; Beijing, China; Department of Biomedical Sciences; Texas Tech University School of Pharmacy; Amarillo, TX USA.
authors.forename: Yinhui
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of Nutrition and Health; College of Food Science and Nutritional Engineering; Beijing Key Laboratory of Functional Food from Plant Resources; China Agricultural University; Beijing, China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Yin
authors.affiliation: Department of Biomedical Sciences; Texas Tech University School of Pharmacy; Amarillo, TX USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Hepatobiliary Surgery; The First Affiliated Hospital; Harbin Medical University; Harbin, Heilongjiang China.
authors.forename: Xiaohe
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Nutrition and Health; College of Food Science and Nutritional Engineering; Beijing Key Laboratory of Functional Food from Plant Resources; China Agricultural University; Beijing, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Nutrition and Health; College of Food Science and Nutritional Engineering; Beijing Key Laboratory of Functional Food from Plant Resources; China Agricultural University; Beijing, China.
authors.forename: Chong
authors.initials: C
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine; China Agricultural University; Beijing, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Fan
authors.affiliation: Nanyang Administration of Traditional Chinese Medicine; Nanyang, Henan China.
authors.forename: Yubing
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Department of Biomedical Sciences; Texas Tech University School of Pharmacy; Amarillo, TX USA.
authors.forename: Junxuan
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Nutrition and Health; College of Food Science and Nutritional Engineering; Beijing Key Laboratory of Functional Food from Plant Resources; China Agricultural University; Beijing, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Nutrition and Health; College of Food Science and Nutritional Engineering; Beijing Key Laboratory of Functional Food from Plant Resources; China Agricultural University; Beijing, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Nutrition and Health; College of Food Science and Nutritional Engineering; Beijing Key Laboratory of Functional Food from Plant Resources; China Agricultural University; Beijing, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Nutrition and Health; College of Food Science and Nutritional Engineering; Beijing Key Laboratory of Functional Food from Plant Resources; China Agricultural University; Beijing, China.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects; D006801:Humans; D047348:Hydrolyzable Tannins / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000473:pathology*
chemical_list: D047348:Hydrolyzable Tannins; C435084:pentagalloylglucose; D048031:JNK Mitogen-Activated Protein Kinases
keywords: MAPK8/9/10; PGG; UPR; apoptosis; autophagy; senescence