4.7 Article

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

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Publisher

MDPI
DOI: 10.3390/ijms241511879

Keywords

FUT8 knockdown; core fucosylation; TRAIL-induced apoptosis; DR4; colorectal cancer

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The inhibition of FucT-8 gene can enhance TRAIL-induced apoptosis in CRC cells, and core fucosylation can control the ERK/MAPK pro-survival pathway. Depletion of core fucosylation sensitizes primary tumour SW480 cells to the combination therapy of TRAIL and low doses of chemotherapeutic drugs, while enhances the resistance of FUT8-knockdown metastatic SW620 cells. FucT-8 could be a potential target for increasing apoptosis and drug response in early CRC.
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 & alpha;(1,6)fucosyltransferase (FucT-8), the only enzyme in mammals that transfers the & alpha;(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.

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