Q6, a novel hypoxia-targeted drug, regulates hypoxia-inducible factor signaling via an autophagy-dependent mechanism in hepatocellular carcinoma.
Q6, a novel hypoxia-targeted drug, regulates hypoxia-inducible factor signaling via an autophagy-dependent mechanism in hepatocellular carcinoma.
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Q6 是一种新型缺氧靶向药物，通过自噬依赖性机制调节肝细胞癌中的缺氧诱导因子信号传导
DOI：
10.4161/auto.26838
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发表时间：
2014-01
期刊：
影响因子：
13.3
通讯作者：
Yang B
中科院分区：
文献类型：
--
作者：
Liu XW;Cai TY;Zhu H;Cao J;Su Y;Hu YZ;He QJ;Yang B
肿瘤缺氧是治疗失败的基础，并产生更具侵袭性和转移性的癌症表型。尽管靶向这些低氧环境的治疗方法已经提出多年，但迄今为止，还没有任何方法显示出获得监管批准的治疗价值。在这里，我们证明了一种新的缺氧激活的前药，Q6，在缺氧条件下表现出有效的抗增殖功效，并诱导2个肝细胞癌（HCC）细胞系中的半胱天冬酶依赖性凋亡，在2个正常肝细胞系中未检测到明显的毒性。用Q6处理显著下调HIF 1A [缺氧诱导因子1，α亚基（碱性螺旋-环-螺旋转录因子）]表达和下游靶基因VEGFA（血管内皮生长因子A）的转录。这种双重低氧靶向调节机制导致在2种体内模型中抑制肿瘤生长和血管形成的高效力。有趣的是，自噬依赖性降解途径在Q6诱导的HIF 1A表达减弱中起着至关重要的作用，而不是蛋白酶体依赖性途径，后者通常被认为是HIF 1A翻译后调控的主要机制。通过短干扰RNA（siRNA）或化学抑制剂抑制自噬，阻断了Q6诱导的HIF 1A降解。HIF 1A的自噬降解通过观察HIF 1A与通过自噬降解的泛素结合衔接蛋白SQSTM 1共免疫沉淀而进一步证实。此外，SQSTM 1的沉默抑制Q6诱导的HIF 1A降解。这些结果表明，新型缺氧靶向药物Q6在肝癌治疗中具有潜在的临床应用价值。此外，自噬作为HIF 1A的关键调节因子的鉴定为缺氧相关治疗提供了新的见解。
Tumor hypoxia underlies treatment failure and yields more aggressive and metastatic cancer phenotypes. Although therapeutically targeting these hypoxic environments has been proposed for many years, to date no approaches have shown the therapeutic value to gain regulatory approval. Here, we demonstrated that a novel hypoxia-activated prodrug, Q6, exhibits potent antiproliferative efficacy under hypoxic conditions and induces caspase-dependent apoptosis in 2 hepatocellular carcinoma (HCC) cell lines, with no obvious toxicity being detected in 2 normal liver cell lines. Treatment with Q6 markedly downregulated HIF1A [hypoxia inducible factor 1, α subunit (basic helix-loop-helix transcription factor)] expression and transcription of the downstream target gene, VEGFA (vascular endothelial growth factor A). This dual hypoxia-targeted modulation mechanism leads to high potency in suppressing tumor growth and vascularization in 2 in vivo models. Intriguingly, it is the autophagy-dependent degradation pathway that plays a crucial role in Q6-induced attenuation of HIF1A expression, rather than the proteasome-dependent pathway, which is normally regarded as the predominant mechanism underlying posttranslational regulation of HIF1A. Inhibition of autophagy, either by short interfering RNA (siRNA) or by chemical inhibitors, blocked Q6-induced HIF1A degradation. Autophagic degradation of HIF1A was further confirmed by the observation that HIF1A coimmunoprecipitated with the ubiquitin-binding adaptor protein, SQSTM1, which is degraded through autophagy. Additionally, silencing of SQSTM1 inhibited Q6-induced HIF1A degradation. These findings suggest that the novel hypoxia-targeted agent, Q6, has potential clinical value in the therapy of HCC. Furthermore, the identification of autophagy as a crucial regulator of HIF1A provides new insights into hypoxia-related treatments.
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影响因子：
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