Radiotherapy has been extensively applied in cancer treatment. However, this treatment is ineffective in Hepatocellular carcinoma (HCC) due to lack of radiosensitivity. Unconventional prefoldin RPB5 interactor 1 (URI1) exhibits characteristics similar to those oncoproteins, which promotes survival of cancer cells. As a consequence of the irradiation, the levels of endogenous reactive oxygen species (ROS) rise. In the current study, we analyzed the role of URI1 in the control of ROS levels in HepG2 cells. Upon URI1 overexpression, HepG2 cells significantly suppressed irradiation-induced ROS, which may help cells escape from oxidative toxicity. And our data demonstrated that overexpression of URI1 not only resulted in an increase of autophagic flux, but also resulted in an further increased capacity of autophagy to eliminate ROS. It indicated that URI1 suppressed irradiation-induced ROS through activating autophagy. Moreover, URI1 activated autophagy by promoting the activities of AMP-activated protein kinase (AMPK). Results showed that overexpression of URI1 increased the phosphorylation of AMPKα at the Thr172 residue and the activated-AMPK promoted the phosphorylation of forkhead box O3 (FOXO3) at the Ser253 residue, which significantly induced autophagy. Taken together, our findings provide a mechanism that URI1 suppresses irradiation-induced ROS by activating autophagy through AMPK/FOXO3 signaling pathway. These new molecular insights will provide an important contribution to our better understanding about irradiation insensitivity of HCC.

中文翻译：

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URI1 通过激活肝细胞癌细胞自噬来抑制辐射诱导的活性氧 (ROS)

放射治疗已广泛应用于癌症治疗。然而，由于缺乏放射敏感性，这种治疗对肝细胞癌（HCC）无效。非常规的前折叠蛋白 RPB5 相互作用蛋白 1 (URI1) 表现出与癌蛋白相似的特征，可促进癌细胞的存活。辐照的结果是，内源性活性氧 (ROS) 水平升高。在当前的研究中，我们分析了 URI1 在控制 HepG2 细胞中 ROS 水平的作用。当 URI1 过度表达时，HepG2 细胞显着抑制辐射诱导的 ROS，这可能有助于细胞逃避氧化毒性。我们的数据表明，URI1 的过度表达不仅导致自噬通量增加，而且还导致自噬消除 ROS 的能力进一步增强。表明URI1通过激活自噬抑制辐射诱导的ROS。此外，URI1通过促进AMP激活蛋白激酶（AMPK）的活性来激活自噬。结果显示，URI1的过表达增加了AMPKα在Thr172残基处的磷酸化，激活的AMPK促进了叉头盒O3（FOXO3）在Ser253残基处的磷酸化，从而显着诱导自噬。综上所述，我们的研究结果提供了一种机制，即 URI1 通过 AMPK/FOXO3 信号通路激活自噬来抑制辐射诱导的 ROS。这些新的分子见解将为我们更好地了解 HCC 的辐射不敏感性做出重要贡献。