• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>Oncotarget >Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer
【2h】

Stromal remodeling by the BET bromodomain inhibitor JQ1 suppresses the progression of human pancreatic cancer

机译：BET溴结构域抑制剂JQ1促基质重塑抑制人胰腺癌的进展

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Inhibitors of bromodomain and extraterminal domain (BET) proteins, a family of chromatin reader proteins, have therapeutic efficacy against various malignancies. However, the detailed mechanisms underlying the anti-tumor effects in distinct tumor types remain elusive. Here, we show a novel antitumor mechanism of BET inhibition in pancreatic ductal adenocarcinoma (PDAC). We found that JQ1, a BET inhibitor, decreased desmoplastic stroma, a hallmark of PDAC, and suppressed the growth of patient-derived tumor xenografts (PDX) of PDACs. In vivo antitumor effects of JQ1 were not always associated with the JQ1 sensitivity of respective PDAC cells, and were rather dependent on the suppression of tumor-promoting activity in cancer-associated fibroblasts (CAFs). JQ1 inhibited Hedgehog and TGF-β pathways as potent regulators of CAF activation and suppressed the expression of α-SMA, extracellular matrix, cytokines, and growth factors in human primary CAFs. Consistently, conditioned media (CM) from CAFs promoted the proliferation of PDAC cells along with the activation of ERK, AKT, and STAT3 pathways, though these effects were suppressed when CM from JQ1-treated CAFs was used. Mechanistically, chromatin immunoprecipitation experiments revealed that JQ1 reduced TGF-β–dependent gene expression by disrupting the recruitment of the transcriptional machinery containing BET proteins. Finally, combination therapy with gemcitabine plus JQ1 showed greater efficacy than gemcitabine monotherapy against PDAC in vivo. Thus, our results reveal BET proteins as the critical regulators of CAF-activation and also provide evidence that stromal remodeling by epigenetic modulators can be a novel therapeutic option for PDAC.
机译：溴结构域和末端外结构域（BET）蛋白（染色质阅读器蛋白家族）的抑制剂具有针对各种恶性肿瘤的治疗功效。但是，在不同的肿瘤类型中抗肿瘤作用的详细机制仍不清楚。在这里，我们显示了胰腺导管腺癌（PDAC）中BET抑制的新型抗肿瘤机制。我们发现JQ1（一种BET抑制剂）减少了增生基质（PDAC的标志），并抑制了PDAC的患者肿瘤异种移植物（PDX）的生长。 JQ1的体内抗肿瘤作用并不总是与各个PDAC细胞的JQ1敏感性相关，而是取决于癌症相关成纤维细胞（CAF）中肿瘤促进活性的抑制。 JQ1抑制刺猬和TGF-β通路作为CAF激活的有效调节剂，并抑制人原发性CAF中α-SMA，细胞外基质，细胞因子和生长因子的表达。一致地，来自CAF的条件培养基（CM）促进PDAC细胞的增殖以及ERK，AKT和STAT3途径的激活，尽管使用来自JQ1处理的CAF的CM抑制了这些作用。从机制上讲，染色质免疫沉淀实验表明JQ1通过破坏包含BET蛋白的转录机制的募集而降低了TGF-β依赖性基因的表达。最后，吉西他滨联合JQ1的联合疗法在体内对PDAC的疗效优于吉西他滨单一疗法。因此，我们的结果揭示了BET蛋白是CAF激活的关键调节因子，并且还提供了证据表明表观遗传调节剂进行基质重塑可能是PDAC的新型治疗选择。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号