title: Ampelopsin induces cell growth inhibition and apoptosis in breast cancer cells through ROS generation and endoplasmic reticulum stress pathway.
abstract: Ampelopsin (AMP), a major bioactive constituent of Ampelopsis grossedentata, exerts a number of biological effects. In this study, we investigated its anti-cancer activity in human breast cancer cell lines, and explored the underlying mechanism of this action. Our results showed that treatment with AMP dose-dependently inhibited cell viability and induced apoptosis in MCF-7 and MDA-MB-231 breast cancer cells without cytotoxicity in human normal breast epithelial cells MCF-10A. Meanwhile, AMP dose- dependently triggered reactive oxygen species (ROS) generation in both breast cancer cells. The ROS scavenger N-acetyl-L-cysteine (NAC) strongly attenuated AMP-induced ROS production, along with cell growth inhibition and apoptosis. Furthermore, AMP was observed to activate endoplasmic reticulum (ER) stress, as evidenced by the up-regulation of ER stress-related proteins, including GRP78, p-PERK, p-elF2α, cleaved ATF6α and CHOP, while knockdown of ATF6α or PERK markedly down-regulated AMP-induced CHOP expression. Blocking ER stress using 4-phenylbutyric acid not only down-regulated AMP-induced GRP78 and CHOP expression, but also significantly decreased AMP-induced cell growth inhibition and apoptosis, whereas ER stress inducer thapsigargin played opposing effects. Additionally, NAC inhibited AMP-induced ER stress by down-regulating GRP78 and CHOP expression. Conversely, blocking ER stress using CHOP siRNA decreased AMP-induced ROS production and cell apoptosis. Taken together, these results demonstrate that AMP has anti-tumor effects against breast cancer cells through ROS generation and ER stress pathway, which therefore provide experimental evidences for developing AMP as a new therapeutic drug for breast cancer.
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Research Center for Medical Nutrition, Chongqing, P.R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Research Center for Medical Nutrition, Chongqing, P.R. China.
authors.forename: Furong
authors.initials: F
authors.lastname: Shu
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Research Center for Medical Nutrition, Chongqing, P.R. China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Liang
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Research Center for Medical Nutrition, Chongqing, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Chang
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Research Center for Medical Nutrition, Chongqing, P.R. China.
authors.forename: Linying
authors.initials: L
authors.lastname: Shi
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Research Center for Medical Nutrition, Chongqing, P.R. China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Peng
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Research Center for Medical Nutrition, Chongqing, P.R. China.
authors.forename: Jundong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Research Center for Nutrition and Food Safety, Institute of Military Preventive Medicine, Third Military Medical University, Chongqing Key Laboratory of Nutrition and Food Safety, Research Center for Medical Nutrition, Chongqing, P.R. China.
authors.forename: Mantian
authors.initials: M
authors.lastname: Mi
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D032421:Ampelopsis / Q000737:chemistry; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D005260:Female; D005419:Flavonoids / Q000302:isolation & purification / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010654:Phenylbutyrates / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000972:Antineoplastic Agents, Phytogenic; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D005419:Flavonoids; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D010654:Phenylbutyrates; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014157:Transcription Factors; D051742:Transcription Factor CHOP; C101003:ELF2 protein, human; C106407:ampelopsin; D019284:Thapsigargin; C075773:4-phenylbutyric acid; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase; D000111:Acetylcysteine