Wogonin induced calreticulin/annexin A1 exposure dictates the immunogenicity of cancer cells in a PERK/AKT dependent manner.
Wogonin induced calreticulin/annexin A1 exposure dictates the immunogenicity of cancer cells in a PERK/AKT dependent manner.
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汉黄芩素诱导的钙网蛋白/膜联蛋白 A1 暴露以 PERK/AKT 依赖性方式决定癌细胞的免疫原性
DOI：
10.1371/journal.pone.0050811
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
You QD
中科院分区：
文献类型：
--
作者：
Yang Y;Li XJ;Chen Z;Zhu XX;Wang J;Zhang LB;Qiang L;Ma YJ;Li ZY;Guo QL;You QD
在电离辐射和某些化疗药物的作用下，垂死的肿瘤细胞会引发一种强有力的抗癌免疫反应。然而，沃根素（5,7-二羟基-8-甲氧基黄酮）对癌症免疫原性的潜在影响尚未得到研究。本研究首次证明了wogonin通过诱导钙网蛋白（CRT）和膜联蛋白A1向细胞质膜的易位以及高迁移率组蛋白1 （HMGB1）和ATP的释放而具有有效的抗肿瘤免疫作用。研究了参与这一过程的信号通路。我们发现wogonin诱导的活性氧（ROS）产生引起内质网（ER）应激反应，包括PERK（类内质网激酶）/PKR（蛋白激酶R）和eIF2α（真核起始因子2α）的磷酸化，这些磷酸化是磷酸化肌肽3-激酶(PI3K)/AKT的上游信号，诱导钙网蛋白(CRT)/膜联蛋白A1细胞膜易位。P22/CHP是一种Ca2+结合蛋白，与CRT相关，并且是CRT转运到细胞膜所必需的。wogonin处理的MFC细胞单独或与其他可能的因子共同释放HMGB1和ATP，激活树突状细胞并诱导细胞因子释放。体内研究证实，用沃戈宁预处理的肿瘤细胞接种免疫可显著抑制小鼠同种异体移植胃肿瘤的生长，并可能涉及炎症反应。综上所述，内质膜应激诱导的CRT/Annexin A1易位（“吃我”信号）和HMGB1释放激活PI3K通路，介导了wogonin诱导的肿瘤细胞疫苗免疫。这表明沃戈宁是一种新的有效的胃肿瘤免疫治疗候选药物。
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.
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HMGB1：内源性危险信号。
影响因子：
5.7
作者：
Klune, John R.;Dhupar, Rajeev;Cardinal, Jon;Billiar, Timothy R.;Tsung, Allan
通讯作者：
Tsung, Allan
影响因子：
3.7
作者：
Kuraishi, Takayuki;Manaka, Junko;Nakanishi, Yoshinobu
通讯作者：
Nakanishi, Yoshinobu
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.8
作者：
Arur, S;Uche, UE;Han, DK
通讯作者：
Han, DK
影响因子：
2.9
作者：
Hosoi, Toru;Hyoda, Kanae;Ozawa, Koichiro
通讯作者：
Ozawa, Koichiro