Core Fucosylation Mediated by the FucT-8 Enzyme Affects TRAIL-Induced Apoptosis and Sensitivity to Chemotherapy in Human SW480 and SW620 Colorectal Cancer Cells

Author:

López-Cortés Rubén1ORCID,Correa Pardo Isabel2,Muinelo-Romay Laura3ORCID,Fernández-Briera Almudena4,Gil-Martín Emilio4ORCID

Affiliation:

1. Doctoral Program in Methods and Applications in Life Sciences, Faculty of Biology, Universidade de Vigo, Campus Lagoas-Marcosende, ES36310 Vigo, Spain

2. Master Program in Advanced Biotechnology, Faculty of Biology, Universidade de Vigo, Campus Lagoas-Marcosende, ES36310 Vigo, Spain

3. Liquid Biopsy Analysis Unit, Translational Medical Oncology (Oncomet), Health Research Institute of Santiago de Compostela (IDIS), CIBERONC, Travesía da Choupana, ES15706 Santiago de Compostela, Spain

4. Department of Biochemistry, Genetics and Immunology, Faculty of Biology, Universidade de Vigo, Campus Lagoas-Marcosende, ES36310 Vigo, Spain

Abstract

Epithelial cells can undergo apoptosis by manipulating the balance between pro-survival and apoptotic signals. In this work, we show that TRAIL-induced apoptosis can be differentially regulated by the expression of α(1,6)fucosyltransferase (FucT-8), the only enzyme in mammals that transfers the α(1,6)fucose residue to the pentasaccharide core of complex N-glycans. Specifically, in the cellular model of colorectal cancer (CRC) progression formed using the human syngeneic lines SW480 and SW620, knockdown of the FucT-8-encoding FUT8 gene significantly enhanced TRAIL-induced apoptosis in SW480 cells. However, FUT8 repression did not affect SW620 cells, which suggests that core fucosylation differentiates TRAIL-sensitive premetastatic SW480 cells from TRAIL-resistant metastatic SW620 cells. In this regard, we provide evidence that phosphorylation of ERK1/2 kinases can dynamically regulate TRAIL-dependent apoptosis and that core fucosylation can control the ERK/MAPK pro-survival pathway in which SW480 and SW620 cells participate. Moreover, the depletion of core fucosylation sensitises primary tumour SW480 cells to the combination of TRAIL and low doses of 5-FU, oxaliplatin, irinotecan, or mitomycin C. In contrast, a combination of TRAIL and oxaliplatin, irinotecan, or bevacizumab reinforces resistance of FUT8-knockdown metastatic SW620 cells to apoptosis. Consequently, FucT-8 could be a plausible target for increasing apoptosis and drug response in early CRC.

Funder

Ministerio de Educación y Ciencia, Spain

Contrato-Programa de Consolidación de Unidades de Investigación Competitivas

Contrato-Programa de Consolidación de Grupos de Referencia Competitiva

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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