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 Ca2+-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.
Highlights
Traditional cancer treatment methods include surgery, radiation therapy, chemotherapy, and for some cancer types, hormone therapy
We found that Endoplasmic Reticulum (ER) stress response, including protein kinase R-like endoplasmic reticulum kinase (PERK) (PKR-like endoplasmic reticulum kinase)/PKR and eukaryotic translation initiation factor 2a (eIF2a) phosphorylation and the subsequent activation of phosphoinositide 3-kinase (PI3K)/AKT signaling pathway are involve in this process
We found that wogonin induces CRT translocation to cell plasma surface, PERK and PI3K/AKT might be involved in this process
Summary
Traditional cancer treatment methods include surgery, radiation therapy, chemotherapy, and for some cancer types, hormone therapy. The benefits are obtained by many patients, they are rarely curative for the very few residual disseminated tumor cells, the primary cause of death among cancer patients. An important reason why tumors are not controlled by the immune system is that the low immunogenicity. The use of cancer vaccines to elicit a therapeutic antitumor immune response against judiciously chosen tumor antigens expressed in the tumor cells can seek out and kill the disseminated tumor cells. One possible strategy for achieving this involves immunization with tumor cells that have been treated with a particular class of chemotherapeutic drugs. Accumulating evidence indicates that several chemotherapeutic agents (including anthracyclines and oxaliplatin), and ionizing irradiation (such as c-rays and ultraviolet C (UVC) light) induce immunogenic cancer cell death [1,2]. The elements of the pathway mediating pre-apoptotic CRT exposure involve a pool of CRT that transited the Golgi apparatus and secreted by SNARE-dependent exocytosis [4]
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