title: Juglanthraquinone C Induces Intracellular ROS Increase and Apoptosis by Activating the Akt/Foxo Signal Pathway in HCC Cells.
abstract: Juglanthraquinone C (JC), a naturally occurring anthraquinone extracted from Juglans mandshurica, could induce apoptosis of cancer cells. This study aims to investigate the detailed cytotoxicity mechanism of JC in HepG2 and BEL-7402 cells. The Affymetrix HG-U133 Plus 2.0 arrays were first used to analyze the mRNA expression exposed to JC or DMSO in HepG2 cells. Consistent with the previous results, the data indicated that JC could induce apoptosis and hyperactivated Akt. The Western blot analysis further revealed that Akt, a well-known survival protein, was strongly activated in HepG2 and BEL-7402 cells. Furthermore, an obvious inhibitory effect on JC-induced apoptosis was observed when the Akt levels were decreased, while the overexpression of constitutively active mutant Akt greatly accelerated JC-induced apoptosis. The subsequent results suggested that JC treatment suppressed nuclear localization and increased phosphorylated levels of Foxo3a, and the overexpression of Foxo3a abrogated JC-induced apoptosis. Most importantly, the inactivation of Foxo3a induced by JC further led to an increase of intracellular ROS levels by suppressing ROS scavenging enzymes, and the antioxidant N-acetyl-L-cysteine and catalase successfully decreased JC-induced apoptosis. Collectively, this study demonstrated that JC induced the apoptosis of hepatocellular carcinoma (HCC) cells by activating Akt/Foxo signaling pathway and increasing intracellular ROS levels.
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China ; Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China ; Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
authors.forename: Ya-Qin
authors.identifier: 0000-0002-1471-3920
authors.initials: YQ
authors.lastname: Hou
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China ; Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu 221002, China.
authors.forename: Yao
authors.identifier: 0000-0002-2905-6425
authors.initials: Y
authors.lastname: Yao
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Yong-Li
authors.identifier: 0000-0002-5972-1983
authors.initials: YL
authors.lastname: Bao
authors.affiliation: Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China.
authors.forename: Zhen-Bo
authors.identifier: 0000-0001-6943-7209
authors.initials: ZB
authors.lastname: Song
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Cheng
authors.identifier: 0000-0002-0992-5187
authors.initials: C
authors.lastname: Yang
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Xiu-Li
authors.identifier: 0000-0001-5022-0157
authors.initials: XL
authors.lastname: Gao
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Wen-Jing
authors.identifier: 0000-0003-0902-2786
authors.initials: WJ
authors.lastname: Zhang
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Lu-Guo
authors.identifier: 0000-0001-8822-3062
authors.initials: LG
authors.lastname: Sun
authors.affiliation: Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
authors.forename: Chun-Lei
authors.identifier: 0000-0002-0471-9261
authors.initials: CL
authors.lastname: Yu
authors.affiliation: Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China.
authors.forename: Yan-Xin
authors.identifier: 0000-0002-4913-8161
authors.initials: YX
authors.lastname: Huang
authors.affiliation: National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China.
authors.forename: Guan-Nan
authors.identifier: 0000-0001-5145-2144
authors.initials: GN
authors.lastname: Wang
authors.affiliation: Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China.
authors.forename: Yu-Xin
authors.identifier: 0000-0002-6889-4050
authors.initials: YX
authors.lastname: Li
mesh_terms: D000880:Anthraquinones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000880:Anthraquinones; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D017382:Reactive Oxygen Species; C575655:juglanthraquinone C; D051057:Proto-Oncogene Proteins c-akt