O-GlcNAcylation protein disruption by Thiamet G promotes changes on the GBM U87-MG cells secretome molecular signature

Clinical Proteomics

John A. Hanover¹  Fernanda Mariath²  Maria Cecilia Oliveira-Nunes³  Aline Menezes⁴  Glaucia Julião⁴  Katia Carneiro⁴  Joseph Albert Medeiros Evaristo⁵  Fábio César Sousa Nogueira⁵  Wagner Barbosa Dias⁶  Denise de Abreu Pereira⁷ 

[1] Laboratory of Cell Biochemistry and Molecular Biology, NIDDK, NIH, Bethesda, MD, USA;Laboratory of Cell Proliferation and Differentiation, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;Laboratory of Cell Proliferation and Differentiation, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA, USA;Laboratory of Cell Proliferation and Differentiation, Institute of Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;Postgraduate Program in Medicine (Pathological Anatomy), Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;Laboratory of Proteomics/LADETEC, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;Laboratory of Structural and Functional Glycobiology, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil;Program of Cellular and Molecular Oncobiology, Membrane Receptors and Cancer Group, Research Coordination, National Institute of Cancer, Rio de Janeiro, RJ, Brazil;

关键词: Glioblastoma;    Secretome;    O-GlcNAcylation;    O-GlcNAcase;   

DOI  :  10.1186/s12014-021-09317-x

来源: Springer

【 摘 要 】

Glioblastoma (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.

【 授权许可】

CC BY