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

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.