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Wogonin Induced Calreticulin/Annexin A1 Exposure Dictates the Immunogenicity of Cancer Cells in a PERK/AKT Dependent Manner
- Source :
- PLoS ONE, PLoS ONE, Vol 7, Iss 12, p e50811 (2012)
- Publication Year :
- 2012
- Publisher :
- Public Library of Science, 2012.
-
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.
- Subjects :
- Cancer Treatment
lcsh:Medicine
Antineoplastic Agents
Gastroenterology and Hepatology
chemistry.chemical_compound
Mice
Phosphatidylinositol 3-Kinases
Wogonin
Neoplasms
Gastrointestinal Cancers
Animals
lcsh:Science
Protein kinase B
PI3K/AKT/mTOR pathway
Annexin A1
Multidisciplinary
biology
Cell Death
Endoplasmic reticulum
lcsh:R
Cell Membrane
Dendritic Cells
Endoplasmic Reticulum Stress
Cell biology
chemistry
Oncology
Flavanones
biology.protein
Unfolded protein response
Medicine
lcsh:Q
Immunotherapy
Signal transduction
Calreticulin
Reactive Oxygen Species
Proto-Oncogene Proteins c-akt
Research Article
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 7
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....b274806b8bf34e6bdfbc2102d4851e4f