title: Wogonin induced calreticulin/annexin A1 exposure dictates the immunogenicity of cancer cells in a PERK/AKT dependent manner.
abstract: In response to ionizing irradiation and certain chemotherapeutic agents, dying tumor cells elicit a potent anticancer immune response. However, the potential effect of wogonin (5,7-dihydroxy-8-methoxyflavone) on cancer immunogenicity has not been studied. Here we demonstrated for the first time that wogonin elicits a potent antitumor immunity effect by inducing the translocation of calreticulin (CRT) and Annexin A1 to cell plasma membrane as well as the release of high-mobility group protein 1 (HMGB1) and ATP. Signal pathways involved in this process were studied. We found that wogonin-induced reactive oxygen species (ROS) production causes an endoplasmic reticulum (ER) stress response, including the phosphorylation of PERK (PKR-like endoplasmic reticulum kinase)/PKR (protein kinase R) and eIF2α (eukaryotic initiation factor 2α), which served as upstream signal for the activation of phosphoinositide 3-kinase (PI3K)/AKT, inducing calreticulin (CRT)/Annexin A1 cell membrane translocation. P22/CHP, a Ca(2+)-binding protein, was associated with CRT and was required for CRT translocation to cell membrane. The releases of HMGB1 and ATP from wogonin treated MFC cells, alone or together with other possible factors, activated dendritic cells and induced cytokine releases. In vivo study confirmed that immunization with wogonin-pretreated tumor cells vaccination significantly inhibited homoplastic grafted gastric tumor growth in mice and a possible inflammatory response was involved. In conclusion, the activation of PI3K pathway elicited by ER stress induced CRT/Annexin A1 translocation ("eat me" signal) and HMGB1 release, mediating wogonin-induced immunity of tumor cell vaccine. This indicated that wogonin is a novel effective candidate of immunotherapy against gastric tumor.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.forename: Xian-Jing
authors.initials: XJ
authors.lastname: Li
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Xuan-Xuan
authors.initials: XX
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Lin-bo
authors.initials: LB
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Qiang
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Ma
authors.forename: Zhi-yu
authors.initials: ZY
authors.lastname: Li
authors.forename: Qing-Long
authors.initials: QL
authors.lastname: Guo
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D037282:Calreticulin / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects* / Q000276:immunology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000276:immunology; D044950:Flavanones / Q000494:pharmacology*; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D017305:Annexin A1; D000970:Antineoplastic Agents; D037282:Calreticulin; D044950:Flavanones; D017382:Reactive Oxygen Species; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C085514:wogonin