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首页> 外文期刊>Journal of Cellular Physiology >LB-1 Exerts Antitumor Activity in Pancreatic Cancer by Inhibiting HIF-1 and Stat3 Signaling
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LB-1 Exerts Antitumor Activity in Pancreatic Cancer by Inhibiting HIF-1 and Stat3 Signaling

机译：LB-1施加在胰腺抗肿瘤活性癌症通过抑制HIF-1和Stat3信号

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Hypoxia is widely present in pancreatic cancer and subsequently causes the overexpression of hypoxia-inducible factor-1 (HIF-1) and signal transducer and activator of transcription-3 (Stat3). HIF-1 and Stat3 function cooperatively to regulate a number of downstream genes that are implicated in tumorigenesis. Thus, inhibition of HIF-1 and Stat3 is a potential therapeutic strategy for pancreatic cancer. In this study, we explored how LB-1, a novel triptolide (LA) derivative, exerted its antitumor effect through blockade of HIF-1 and Stat3 signaling. Our data showed that LB-1 was able to inhibit the proliferation and colony formation of Mia-PaCa2 and SW1990 cells. LB-1 suppressed HIF-1 protein accumulation by promoting its proteasome degradation and reducing transactivation. Moreover, the silence of HIF-1 by shRNA partially prevented the proliferation inhibition triggered by LB-1. As expected, LB-1 also decreased Stat3 protein accumulation and blocked the physical interactions between HIF-1/p300/phosphor-Stat3 (p-Stat3) at the pharmacological concentration to reduce VEGF expression, thereby hypoxia-induced angiogenesis. In the Mia-PaCa2 nude xenograft model, therapeutic treatment with LB-1 significantly inhibited tumor growth and had minimal systemic toxicity compared to the mother drug LA. Furthermore, in accordance with in vitro results, HIF-1 activation and Stat3 expression in tumors were blocked by LB-1 through mTOR-dependent pathway. Taken together, these results illustrate that, as a potent inhibitor of HIF-1 and Stat3 signaling, LB-1 exhibits antitumor effect and could be potentially used to treat pancreatic cancer. J. Cell. Physiol. 230: 2212-2223, 2015. (c) 2015 Wiley Periodicals, Inc.
机译：缺氧是广泛存在于胰腺癌和随后引起的过度低氧诱导因子- 1 (HIF-1)和信号传感器和transcription-3活化剂(Stat3)。规范的下游基因参与肿瘤发生。HIF-1和Stat3是一个潜在的治疗胰腺癌的策略。探索如何LB-1小说triptolide(洛杉矶)导数,对其抗肿瘤效应封锁HIF-1和Stat3信号。表明LB-1能够抑制扩散和Mia-PaCa2集落形成和SW1990细胞。积累通过促进蛋白酶体退化和减少transactivation。此外,沉默的shRNA HIF-1部分防止扩散抑制触发LB-1。蛋白质积累并封锁了身体之间的交互HIF-1 / p300 / phosphor-Stat3(p-Stat3)药物浓度降低VEGF表达,从而诱导血管生成。与LB-1模型,治疗治疗显著抑制肿瘤的生长和最小的系统性毒性比母亲药物。结果,HIF-1激活和Stat3的表达肿瘤被LB-1通过mTOR-dependent途径。结果说明,作为的有效抑制剂HIF-1 Stat3信号,LB-1展品抗肿瘤效应,可能会使用治疗胰腺癌。2212 - 2223年,2015年。

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