Lys05 – A Promising Autophagy Inhibitor in the Radiosensitization Battle: Phosphoproteomic Perspective

Background: Autophagy is a crucial factor contributing to radioresistance during radiotherapy. Although Lys05 has proven its ability to improve the results of radiotherapy through the inhibition of autophagy, molecular mechanisms of this inhibition remain elusive. We aimed to describe the molecular mechanisms involved in Lys05-induced autophagy inhibition.
Materials and Methods: Radioresistant human non-small cell lung carcinoma cells (H1299, p53-negative) and methods of quantitative phosphoproteomics were employed to define the molecular mechanisms involved in Lys05-induced inhibition of autophagy.
Results: We confirmed that at an early stage after irradiation, autophagy was induced, whereas at a later stage after irradiation, it was inhibited. The early-stage induction of autophagy was characterized mainly by the activation of biosynthetic and metabolic processes through up- or down-regulation of the critical autophagic regulatory proteins Sequestosome-1 (SQSTM1) and Proline-rich AKT1 substrate 1 (AKT1S1). The late-stage inhibition of autophagy was attributed mainly to down-regulation of Unc-51 like autophagy activating kinase 1 (ULK1) through phosphorylation at Ser638.
Conclusion: This work contributes to emerging phosphoproteomic insights into autophagy-mediated global signaling in lung cancer cells, which might consequently facilitate the development of precision medicine therapeutics.

背景：自噬是放疗期间产生放射耐受性的关键因素。尽管Lys05已证明其通过抑制自噬来改善放疗结果的能力，但其抑制作用的分子机制尚不明确。本研究旨在描述Lys05诱导的自噬抑制涉及的分子机制。
材料与方法：采用放射耐受性人非小细胞肺癌细胞（H1299，p53阴性）和定量磷酸化蛋白质组学方法，以定义Lys05诱导的自噬抑制涉及的分子机制。
结果：我们证实，在照射早期阶段，自噬被诱导，而在照射后期阶段，自噬被抑制。早期阶段自噬的诱导主要表现为通过上调或下调关键的自噬调控蛋白Sequestosome-1（SQSTM1）和脯氨酸富集的AKT1底物1（AKT1S1）的活性，激活生物合成和代谢过程。后期阶段自噬的抑制主要归因于ULK1（Unc-51样自噬激活激酶1）通过Ser638位点的磷酸化而下调。
结论：本研究为自噬介导的肺癌细胞全局信号传导的磷酸化蛋白质组学新见解做出了贡献，这可能会进一步促进精准医学治疗的发展。