title: 7-O-Geranylquercetin induces apoptosis in gastric cancer cells via ROS-MAPK mediated mitochondrial signaling pathway activation.
abstract: 7-O-Geranylquercetin (GQ) is a novel O-alkylated derivate of quercetin. In this study, we evaluated its apoptosis induction effects in human gastric cancer cell lines SGC-7901 and MGC-803 and explored the potential molecular mechanisms. The results demonstrated that GQ lowered viability of SGC-7901 and MGC-803 cells in a dose- and time-dependent manner without apparent cytotoxicity to human gastric epithelial cell line GES-1. GQ could induce apoptosis in SGC-7901 and MGC-803cells, and arrest the gastric cancer cells at G2/M phase. Mechanism study showed that GQ triggered generation of reactive oxygen species (ROS), then activated p38 and JNK signaling pathways, subsequently led to mitochondrial impairment by regulating the expression of Bcl-2, Bcl-xl and Bax, and finally promoted the release of cytochrome c and the activation of caspases to induce apoptosis. In addition, Z-VAD-FMK (caspase inhibitor) could reverse GQ-induced apoptosis. SB203580 (p38 inhibitor) and SP600125 (JNK inhibitor) could rescue GQ-induced cell death and attenuate mitochondrial signal pathway activation. Furthermore, NAC (ROS inhibitor) could rescue GQ-induced cell death, reduce ROS generation, decrease the phosphorylation of p38 and JNK, and then attenuate the activation of mitochondrial signal pathway. Taken together, GQ induces caspase-dependent apoptosis in gastric cancer cells through activating ROS-MAPK mediated mitochondrial signal pathway. This study highlights the potential use of GQ as a gastric cancer therapeutic agent.
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Yameng
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Linying
authors.initials: L
authors.lastname: Du
authors.affiliation: SEAC-ME Key Laboratory of Biotechnology and Bio-resources Utilization, Dalian Minzu University, Dalian 116600, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xu
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Enxia
authors.initials: E
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Sun
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Guo
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Boyang
authors.initials: B
authors.lastname: Zou
authors.affiliation: College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Wang
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China.
authors.forename: Changyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Affiliated Dalian Friendship Hospital of Dalian Medical University, No. 8 Sanba Square, Zhongshan District, Dalian, 116001, China. Electronic address: summer150495@sohu.com.
authors.forename: Lidan
authors.initials: L
authors.lastname: Sun
authors.affiliation: College of Pharmacy, Dalian Medical University, Dalian, 116044, China. Electronic address: zhenyhwaner@aliyun.com.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Zhen
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000607199:7-O-geranylquercetin; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D011794:Quercetin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: 7-O-Geranylquercetin; Apoptosis; Gastric cancer; MAPK; Mitochondria; Reactive oxygen species