Novel autophagy inhibitor Lys05 enhances impact of ionizing radiation on human lung cancer cells H1299
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ABSTRACT:
PROVIDER: PRJNA576671 | ENA |
REPOSITORIES: ENA
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Project description:Autophagy inhibition through small-molecule inhibitors is one of the approaches to increasing the efficiency of radiotherapy of oncological patients. A new inhibitor, Lys05, with potential to accumulate within lysosomes and to block autophagy has been discovered recently. Several studies have described its chemosensitizing effects, but nothing is known about its impact in the context of ionizing radiation (IR). To investigate the mechanisms underlying its role in radiosensitization we employed radioresistant human non-small cell lung carcinoma cells (H1299, p53-negative) in combination with multiple approaches (cell biology techniques to reveal the phenotypes, and quantitative phosphoproteomics to comprehensively describe Lys05-induced changes in irradiated cells). In the presented study, we report for the first time that Lys05 could be utilized in combination with IR as a promising future strategy in eradication of lung cancer cells.
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Project description:microRNA regulates cellular responses to ionizing radiation (IR) through the translational control of target genes. We analyzed time-series changes in microRNA expressions upon γ-irradiation in H1299 lung cancer cell lines using microarray. Significantly changed microRNAs were selected based on ANOVA analysis, target genes of which were enriched to MAPK signaling pathway. Concurrent analysis of mRNA and microRNA uncovered that the expression of miR-26b and its target ATF2 mRNA were inversely correlated in γ-irradiated H1299 cells. The overexpression of miR-26b induced the suppression of ATF2 in γ-irradiated cells. When we inhibit the MAPK signaling pathway using SP600125, JNK inhibitor, the expression of miR-26b was induced even in γ-irradiated H1299 cells. From these results, we concluded that the expression of miR-26b was coordinated regulated by MAPK signaling pathway upon ionizing radiation, and MAPK signaling pathway was regulated by miR-26b in turn. We analyzed the time-series miRNA profiles of radioresistant H1299 cells in response to 2 Gy of ionizing radiation (IR) by performing quadratic regression (QR) analysis to identify genes associated with radioresistance
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Project description:Objective: to find out the exosome miRNA of H1299 cells that can be changed by ionizing radiation
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Project description:microRNA regulates cellular responses to ionizing radiation (IR) through the translational control of target genes. We analyzed time-series changes in microRNA expressions upon γ-irradiation in H1299 lung cancer cell lines using microarray. Significantly changed microRNAs were selected based on ANOVA analysis, target genes of which were enriched to MAPK signaling pathway. Concurrent analysis of mRNA and microRNA uncovered that the expression of miR-26b and its target ATF2 mRNA were inversely correlated in γ-irradiated H1299 cells. The overexpression of miR-26b induced the suppression of ATF2 in γ-irradiated cells. When we inhibit the MAPK signaling pathway using SP600125, JNK inhibitor, the expression of miR-26b was induced even in γ-irradiated H1299 cells. From these results, we concluded that the expression of miR-26b was coordinated regulated by MAPK signaling pathway upon ionizing radiation, and MAPK signaling pathway was regulated by miR-26b in turn.
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Project description:This project explored the relationship between ionizing radiation and antigen presentation using both proteomic and immunopeptidomics methodologies. We investigated the radiation-specific changes which occur in the colorectal tumor cell proteome associated with changes in dose and time after irradiation. We used this data to observe the changes in key regulators and effector proteins of the antigen processing and presentation machinery. Furthermore, a parallel immunopeptidomics analysis enabled a peptide-level assessment of antigen presentation to correlate changes observed in the proteome thereby defining a radiation-specific peptide repertoire. A nuanced relationship between protein expression and antigen presentation was observed where radiation-induced changes in proteins do not always correlate with increased presentation of associated peptides. Furthermore, a neoantigen which increases in the context of radiation was characterised. This study provides new insights into how radiation enhances antigen processing and presentation that could be suitable for the development of combinatorial therapies.
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Project description:To identify a set of genes related to radioresistance, we analyzed the time-series gene expression profiles of radioresistant H1299 and radiosensitive H460 lung cancer cells in response to 2 Gy of ionizing radiation (IR) by performing quadratic regression (QR) analysis. Out of the 21,331 genes, we selected 6,538 genes by QR analysis from the gene expression profile of H460 cells and 6,086 genes from that of H1299 cells. Most of the genes identified in the H460 cells were classified into continuously up- or down-regulated groups, while the major QR groups were transiently changed groups in the H1299 cell line. From gene ontology analysis of the major QR groups, the DNA damage response was commonly enriched in both cell lines. DNA repair-related genes such as ATM, ATR, TP53BP1, BRCA1, MRE11, NBN and RAD50 were particularly up-regulated in H1299 cells. Suppression of these DNA repair-related genes using siRNA made H1299 cells radiosensitive to ionizing radiation. The data suggest that differential responses to DNA damage confer radioresistance to cancer cells, and provide potential novel targets for sensitizing radiotherapy.
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Project description:Autophagy inhibition through small-molecule inhibitors is one of the approaches to increase the efficiency of radiotherapy in oncological patients. A new inhibitor-Lys05-with the potential to accumulate within lysosomes and to block autophagy was discovered a few years ago. Several studies have addressed its chemosensitizing effects but nothing is known about its impact in the context of ionizing radiation (IR). To describe its role in radiosensitization, we employed radioresistant human non-small cell lung carcinoma cells (H1299, p53-negative). Combined treatment of H1299 cells by Lys05 together with IR decreased cell survival in the clonogenic assay and real-time monitoring of cell growth more than either Lys05 or IR alone. Immunodetection of LC3 and p62/SQSTM1 indicated that autophagy was inhibited, which correlated with increased SQSTM1 and decreased BNIP3 gene expression determined by qRT-PCR. Fluorescence microscopy and flow cytometry uncovered an accumulation of lysosomes. Similarly, transmission electron microscopy demonstrated the accumulation of autophagosomes confirming the ability of Lys05 to potentiate autophagy inhibition in H1299 cells. We report here for the first time that Lys05 could be utilized in combination with IR as a promising future strategy in the eradication of lung cancer cells.
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