ST6Gal1 targets the ectodomain of ErbB2 in a site-specific manner and regulates gastric cancer cell sensitivity to trastuzumab

• Tipo: Artigo em Revista Científica Internacional
• Data: 2021

Autores

Duarte, HO (Autor) Outra; Rodrigues, JG (Autor) Outra; Gomes, C (Autor) Outra; Hensbergen, PJ (Autor) Outra; Ederveen, ALH (Autor) Outra; de Ru, AH (Autor) Outra; Mereiter, S (Autor) Outra; Polonia, A (Autor) Outra; Fernandes, E (Autor) Outra; Ferreira, JA (Autor) Outra; van Veelen, PA (Autor) Outra; Santos, LL (Autor) Outra; Wuhrer, M (Autor) Outra; Gomes, J (Autor) Outra; Celso Reis (Autor) ICBAS

Revista

Título: Oncogene

Vol. 40

Páginas: 3719-3733

ISSN: 0950-9232

Editora: Springer Nature

Indexação

ISI Web of Knowledge - 15 Citações

Scopus - 16 Citações

Outras Informações

ID Authenticus: P-00T-WZ9

DOI: 10.1038/s41388-021-01801-w

Abstract (EN): The clinical performance of the therapeutic monoclonal antibody trastuzumab in the treatment of ErbB2-positive unresectable gastric cancer (GC) is severely hampered by the emergence of molecular resistance. Trastuzumab's target epitope is localized within the extracellular domain of the oncogenic cell surface receptor tyrosine kinase (RTK) ErbB2, which is known to undergo extensive N-linked glycosylation. However, the site-specific glycan repertoire of ErbB2, as well as the detailed molecular mechanisms through which specific aberrant glycan signatures functionally impact the malignant features of ErbB2-addicted GC cells, including the acquisition of trastuzumab resistance, remain elusive. Here, we demonstrate that ErbB2 is modified with both alpha 2,6- and alpha 2,3-sialylated glycan structures in GC clinical specimens. In-depth mass spectrometry-based glycomic and glycoproteomic analysis of ErbB2's ectodomain disclosed a site-specific glycosylation profile in GC cells, in which the ST6Gal1 sialyltransferase specifically targets ErbB2 N-glycosylation sites occurring within the receptor's trastuzumab-binding domain. Abrogation of ST6Gal1 expression reshaped the cellular and ErbB2-specific glycomes, expanded the cellular half-life of the ErbB2 receptor, and sensitized ErbB2-dependent GC cells to trastuzumab-induced cytotoxicity through the stabilization of ErbB dimers at the cell membrane, and the decreased activation of both ErbB2 and EGFR RTKs. Overall, our data demonstrates that ST6Gal1-mediated aberrant alpha 2,6-sialylation actively tunes the resistance of ErbB2-driven GC cells to trastuzumab.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 15