HMGB1 induction of clusterin creates a chemoresistant niche in human prostate tumor cells.
HMGB1 induction of clusterin creates a chemoresistant niche in human prostate tumor cells.
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DOI：
10.1038/srep15085
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发表时间：
2015-10-15
影响因子：
4.6
通讯作者：
Djeu JY
中科院分区：
文献类型：
--
作者：
Zhou J;Chen X;Gilvary DL;Tejera MM;Eksioglu EA;Wei S;Djeu JY
化疗耐药，尤其是对多西他赛（DTX）的耐药是去势抵抗性前列腺癌治疗的主要障碍，但其机制尚不清楚。在这里，我们报告了在DTX治疗过程中死亡和残留的活肿瘤细胞之间的种子串扰，这可能导致化疗耐药人群的生长。存活是由于诱导分泌/细胞质簇蛋白（sCLU），这是一种有效的抗凋亡蛋白，已知结合和隔离Bax从线粒体，以防止半胱天冬酶3激活。活细胞中sCLU的诱导依赖于死亡细胞释放HMGB 1。DTX处理的DU 145肿瘤细胞的上清液显示含有HMGB 1，有效地诱导来自新接种的DU 145肿瘤细胞的sCLU，并保护它们免受DTX毒性。在培养上清中加入抗HMBG 1抗体或用抗TLR 4抗体或抗HMBG 1抗体预处理新接种的DU 145肿瘤细胞，可显著消除sCLU诱导和培养上清的保护作用。HMGB 1通过激活NFκB，促进sCLU基因表达，阻止Bax向线粒体转位，阻断细胞死亡。重要的是，目前使用的多种化疗药物可以从肿瘤细胞中释放HMGB 1。这些结果表明，化疗耐药性的获得可能涉及由垂死细胞触发的HMGB 1/TLR 4-p53/sCLU通路，从而为残余的活肿瘤细胞提供存活优势。
Development of chemoresistance, especially to docetaxel (DTX), is the primary barrier to the cure of castration-resistant prostate cancer but its mechanism is obscure. Here, we report a seminal crosstalk between dying and residual live tumor cells during treatment with DTX that can result in outgrowth of a chemoresistant population. Survival was due to the induction of secretory/cytoplasmic clusterin (sCLU), which is a potent anti-apoptotic protein known to bind and sequester Bax from mitochondria, to prevent caspase 3 activation. sCLU induction in live cells depended on HMGB1 release from dying cells. Supernatants from DTX-treated DU145 tumor cells, which were shown to contain HMGB1, effectively induced sCLU from newly-plated DU145 tumor cells and protected them from DTX toxicity. Addition of anti-HMBG1 to the supernatant or pretreatment of newly-plated DU145 tumor cells with anti-TLR4 or anti-RAGE markedly abrogated sCLU induction and protective effect of the supernatant. Mechanistically, HMGB1 activated NFκB to promote sCLU gene expression and prevented the translocation of activated Bax to mitochondria to block cell death. Importantly, multiple currently-used chemotherapeutic drugs could release HMGB1 from tumor cells. These results suggest that acquisition of chemoresistance may involve the HMGB1/TLR4-RAGE/sCLU pathway triggered by dying cells to provide survival advantage to remnant live tumor cells.