Hypoxia-Mediated Sorafenib Resistance Can Be Overcome by EF24 Through Von Hippel-Lindau Tumor Suppressor-Dependent HIF-1α Inhibition in Hepatocellular Carcinoma
Hypoxia-Mediated Sorafenib Resistance Can Be Overcome by EF24 Through Von Hippel-Lindau Tumor Suppressor-Dependent HIF-1α Inhibition in Hepatocellular Carcinoma
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DOI：
10.1002/hep.26224
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发表时间：
2013-05-01
期刊：
影响因子：
13.5
通讯作者：
Liu, Lianxin
中科院分区：
文献类型：
--
作者：
Liang, Yingjian;Zheng, Tongsen;Liu, Lianxin
肝细胞癌（HCC）的发病率不断增加，不仅在美国，而且在全世界都受到极大关注。尽管索拉非尼是一种具有抗血管生成和抗增殖作用的多激酶抑制剂，目前为晚期HCC设定了新的标准，但肿瘤反应率通常很低。了解索拉非尼耐药的潜在机制是至关重要的，如果要改善结果。在这项研究中，我们测试了这一假设，即持续索拉非尼治疗的抗血管生成作用引起的缺氧可诱导索拉非尼耐药作为细胞保护性适应性反应，从而限制索拉非尼的效率。我们发现临床上对索拉非尼耐药的HCC与治疗前的HCC或对索拉非尼敏感的HCC相比，表现出增加的瘤内缺氧。低氧保护HCC细胞对抗索拉非尼，并且低氧诱导因子1（HIF-1 α）是该过程所必需的。低氧条件下，肝癌细胞P-gp表达增加，糖酵解代谢增强，核因子-κ B（NF-κ B）活性增加。EF 24是一种与姜黄素具有结构相似性的分子，通过将其隔离在细胞质中抑制HIF-1 α并通过上调Von Hippel-Lindau肿瘤抑制因子（VHL）促进降解，可以协同增强索拉非尼的抗肿瘤作用并克服索拉非尼抗性。此外，我们发现持续索拉非尼治疗导致肿瘤内缺氧增加，这与肝癌皮下小鼠肿瘤模型中索拉非尼敏感性相关。EF 24和索拉非尼的组合在体内和体外均显示出抗转移的协同作用。在皮下和原位肝肿瘤中也观察到协同肿瘤生长抑制作用。结论：索拉非尼B持续治疗诱导的缺氧通过HIF-1 α和NF-κ B活化赋予索拉非尼B对HCC的抗性。EF 24通过VHL依赖性HIF-1 α降解和NF-κ B失活克服索拉非尼B耐药性。EF 24联合索拉非尼代表了HCC的一种有前途的策略。（肝脏学2013;57：1847-1857）
The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world. Although sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects, currently sets the new standard for advanced HCC, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical if outcomes are to be improved. In this study we tested the hypothesis that hypoxia caused by the antiangiogenic effects of sustained sorafenib therapy could induce sorafenib resistance as a cytoprotective adaptive response, thereby limiting sorafenib efficiency. We found that HCCs, clinically resistant to sorafenib, exhibit increased intratumor hypoxia compared with HCCs before treatment or HCCs sensitive to sorafenib. Hypoxia protected HCC cells against sorafenib and hypoxia-inducible factor 1 (HIF-1 alpha) was required for the process. HCC cells acquired increased P-gp expression, enhanced glycolytic metabolism, and increased nuclear factor kappa B (NF-kappa B) activity under hypoxia. EF24, a molecule having structural similarity to curcumin, could synergistically enhance the antitumor effects of sorafenib and overcome sorafenib resistance through inhibiting HIF-1 alpha by sequestering it in cytoplasm and promoting degradation by way of up-regulating Von Hippel-Lindau tumor suppressor (VHL). Furthermore, we found that sustained sorafenib therapy led to increased intratumor hypoxia, which was associated with sorafenib sensitivity in HCC subcutaneous mice tumor models. The combination of EF24 and sorafenib showed synergistically effects against metastasis both in vivo and in vitro. Synergistic tumor growth inhibition effects were also observed in subcutaneous and orthotopic hepatic tumors. Conclusion: Hypoxia induced by sustained sorafenib treatment confers sorafenib resistance to HCC through HIF-1 alpha and NF-kappa B activation. EF24 overcomes sorafenib resistance through VHL-dependent HIF-1 alpha degradation and NF-kappa B inactivation. EF24 in combination with sorafenib represents a promising strategy for HCC. (HEPATOLOGY 2013;57:1847-1857)