Abstract
AbstractGlioblastoma (GBM) is a grade IV glioma highly aggressive and refractory to the therapeutic approaches currently in use. O-GlcNAcylation plays a key role for tumor aggressiveness and progression in different types of cancer; however, experimental evidence of its involvement in GBM are still lacking. Here, we show that O-GlcNAcylation plays a critical role in maintaining the composition of the GBM secretome, whereas inhibition of OGA activity disrupts the intercellular signaling via microvesicles. Using a label-free quantitative proteomics methodology, we identified 51 proteins in the GBM secretome whose abundance was significantly altered by activity inhibition of O-GlcNAcase (iOGA). Among these proteins, we observed that proteins related to proteasome activity and to regulation of immune response in the tumor microenvironment were consistently downregulated in GBM cells upon iOGA. While the proteins IGFBP3, IL-6 and HSPA5 were downregulated in GBM iOGA cells, the protein SQSTM1/p62 was exclusively found in GBM cells under iOGA. These findings were in line with literature evidence on the role of p62/IL-6 signaling axis in suppressing tumor aggressiveness and our experimental evidence showing a decrease in radioresistance potential of these cells. Taken together, our findings provide evidence that OGA activity may regulate the p62 and IL-6 abundance in the GBM secretome. We propose that the assessment of tumor status from the main proteins present in its secretome may contribute to the advancement of diagnostic, prognostic and even therapeutic tools to approach this relevant malignancy.
Funder
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
Publisher
Springer Science and Business Media LLC
Subject
Clinical Biochemistry,Molecular Biology,Molecular Medicine,Clinical Biochemistry,Molecular Biology,Molecular Medicine
Reference51 articles.
1. Ali A, Kim SH, Kim MJ, Choi MY, Kang SS, Cho GJ, Kim YS, Choi JY, Choi WS. O-GlcNAcylation of NF-κB promotes lung metastasis of cervical cancer cells via upregulation of CXCR4 expression. Mol Cells. 2017;40(7):476–84.
2. Almiron Bonnin DA, Havrda MC, Israel MA. Glioma cell secretion: a driver of tumor progression and a potential therapeutic target. Cancer Res. 2018;78(21):6031–9.
3. Azevedo A, Cunha V, Teixeira AL, Medeiros R. IL-6/IL-6R as a potential key signaling pathway in prostate cancer development. World J Clin Oncol. 2011;2(12):384–96.
4. Bjørkøy G, Lamark T, Pankiv S, Øvervatn A, Brech A, Johansen T. Monitoring autophagic degradation of p62/SQSTM1. Methods Enzymol. 2009;452:181–97.
5. Bond MR, Hanover JA. A little sugar goes a long way: the cell biology of O-GlcNAc. J Cell Biol. 2015;208(7):869–80.
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