Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells
Role of the endothelin axis in astrocyte- and endothelial cell-mediated chemoprotection of cancer cells
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DOI：
10.1093/neuonc/nou128
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发表时间：
2014-12-01
期刊：
影响因子：
15.9
通讯作者：
Kim, Sun-Jin
中科院分区：
文献类型：
--
作者：
Kim, Seung Wook;Choi, Hyun Jin;Kim, Sun-Jin
背景最近的证据表明，星形胶质细胞通过刺激这些细胞中抗凋亡基因的上调来保护癌细胞免受化疗。我们研究了MDA-MB-231乳腺癌细胞和H226肺癌细胞中内皮素轴激活协调生存基因表达和化学保护的可能性。使癌细胞、鼠星形胶质细胞和鼠成纤维细胞单独生长，并将内皮素（ET）肽和ET受体（ETAR和ETBR）的表达与共孵育48小时的癌细胞和星形胶质细胞（或癌细胞和成纤维细胞）上的表达进行比较。使用类型特异性内皮素受体拮抗剂来评估ETAR和ETBR对星形胶质细胞诱导的蛋白激酶B（AKT）/促分裂原活化蛋白激酶（MAPK）信号转导通路的激活、抗凋亡基因表达和癌细胞化学保护的贡献。我们还研究了脑内皮细胞和小胶质细胞的化学保护潜力。MDA-MB-231癌细胞和星形胶质细胞之间的间隙连接信号传导刺激癌细胞中白细胞介素6（IL-6）和IL-8表达的上调，这增加了星形胶质细胞的ET-1产生和癌细胞上的ET受体表达。ET-1信号激活AKT/MAPK和上调保护癌细胞免受紫杉醇侵害的存活蛋白。脑内皮细胞介导的癌细胞化学保护也涉及内皮素信号传导。ETAR和ETBR的双重拮抗作用是消除星形胶质细胞和内皮细胞介导的化学保护作用所必需的。星形胶质细胞和癌细胞之间的双向信号传导涉及内皮素轴的上调和激活，其保护癌细胞免受化疗药物诱导的细胞毒性。
Background. Recent evidence suggests that astrocytes protect cancer cells from chemotherapy by stimulating upregulation of antiapoptotic genes in those cells. We investigated the possibility that activation of the endothelin axis orchestrates survival gene expression and chemoprotection in MDA-MB-231 breast cancer cells and H226 lung cancer cells.Methods. Cancer cells, murine astrocytes, and murine fibroblasts were grown in isolation, and expression of endothelin (ET) peptides and ET receptors (ETAR and ETBR) compared with expression on cancer cells and astrocytes (or cancer cells and fibroblasts) that were co-incubated for 48 hours. Type-specific endothelin receptor antagonists were used to evaluate the contribution of ETAR and ETBR to astrocyte-induced activation of the protein kinase B (AKT)/mitogen-activated protein kinase (MAPK) signal transduction pathways, anti-apoptotic gene expression, and chemoprotection of cancer cells. We also investigated the chemoprotective potential of brain endothelial cells and microglial cells.Results. Gap junction signaling between MDA-MB-231 cancer cells and astrocytes stimulates upregulation of interleukin 6 (IL-6) and IL-8 expression in cancer cells, which increases ET-1 production from astrocytes and ET receptor expression on cancer cells. ET-1 signals for activation of AKT/MAPK and upregulation of survival proteins that protect cancer cells from taxol. Brain endothelial cell-mediated chemoprotection of cancer cells also involves endothelin signaling. Dual antagonism of ETAR and ETBR is required to abolish astrocyte-and endothelial cell-mediated chemoprotection.Conclusions. Bidirectional signaling between astrocytes and cancer cells involves upregulation and activation of the endothelin axis, which protects cancer cells from cytotoxicity induced by chemotherapeutic drugs.