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首页> 外文期刊>Biology Open >Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer
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Targeting developmental regulators of zebrafish exocrine pancreas as a therapeutic approach in human pancreatic cancer

机译：靶向斑马鱼外分泌胰腺的发育调节剂作为人类胰腺癌的治疗方法

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Histone deacetylases (HDACs) and RNA polymerase III (POLR3) play vital roles in fundamental cellular processes, and deregulation of these enzymes has been implicated in malignant transformation. Hdacs and Polr3 are required for exocrine pancreatic epithelial proliferation during morphogenesis in zebrafish. We aim to test the hypothesis that Hdacs and Polr3 cooperatively control exocrine pancreatic growth, and combined inhibition of HDACs and POLR3 produces enhanced growth suppression in pancreatic cancer. In zebrafish larvae, combination of a Hdac inhibitor (Trichostatin A) and an inhibitor of Polr3 (ML-60218) synergistically prohibited the expansion of exocrine pancreas. In human pancreatic adenocarcinoma cells, combination of the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and ML-60218 produced augmented suppression of colony formation and proliferation, and induction of cell cycle arrest and apoptotic cell death. The enhanced cytotoxicity was associated with supra-additive upregulation of the pro-apoptotic regulator BAX and the cyclin-dependent kinase inhibitor p21CDKN1A. tRNAs have been shown to have pro-proliferative and anti-apoptotic roles, and SAHA-stimulated expression of tRNAs was reversed by ML-60218. These findings demonstrate that chemically targeting developmental regulators of exocrine pancreas can be translated into an approach with potential impact on therapeutic response in pancreatic cancer, and suggest that counteracting the pro-malignant side effect of HDAC inhibitors can enhance their anti-tumor activity.
机译：组蛋白脱乙酰基酶（HDAC）和RNA聚合酶III（POLR3）在基本细胞过程中起着至关重要的作用，这些酶的失调与恶性转化有关。 Hdacs和Polr3是斑马鱼形态发生过程中外分泌胰腺上皮增殖所必需的。我们旨在检验Hdacs和Polr3协同控制外分泌胰腺生长的假说，同时抑制HDAC和POLR3可以增强胰腺癌的生长抑制作用。在斑马鱼的幼虫中，Hdac抑制剂（Trichostatin A）和Polr3抑制剂（ML-60218）的组合可协同抑制外分泌胰腺的扩张。在人类胰腺腺癌细胞中，HDAC抑制剂亚磺酰苯胺异羟肟酸（SAHA）和ML-60218的组合可增强抑制菌落形成和增殖的能力，并诱导细胞周期停滞和凋亡细胞死亡。细胞毒性增强与促凋亡调节剂BAX和细胞周期蛋白依赖性激酶抑制剂p21CDKN1A的超加性上调有关。已经显示出tRNA具有促增殖和抗凋亡作用，并且ML-60218逆转了SAHA刺激的tRNA表达。这些发现表明，化学靶向外分泌胰腺的发育调节剂可以转化为对胰腺癌的治疗反应具有潜在影响的方法，并表明抵消HDAC抑制剂的恶性副反应可以增强其抗肿瘤活性。

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