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...

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Bibliographic Details
Published in:Cancer genomics & proteomics 2020-07, Vol.17 (4), p.369-382
Main Authors: ONDREJ, MARTIN, CECHAKOVA, LUCIE, FABRIK, IVO, KLIMENTOVA, JANA, TICHY, ALES
Format: Article
Language:English
Subjects:
AKT1 protein
Autophagy
Drug development
Irradiation
Kinases
Lung cancer
Lung carcinoma
Metabolic rate
Molecular modelling
Non-small cell lung carcinoma
p53 Protein
Phagocytosis
Phosphorylation
Precision medicine
Proline
Radiation therapy
Radioresistance
Radiosensitization
Regulatory proteins
Small cell lung carcinoma
Substrate inhibition
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Summary: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 inhibition of autophagy. 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.
ISSN:1109-6535
1790-6245
DOI:10.21873/cgp.20196