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Death receptor 5 is activated by fucosylation in colon cancer cells
Author(s) -
Zhang Baojie,
Roosmalen Ingrid A. M.,
Reis Carlos R.,
Setroikromo Rita,
Quax Wim J.
Publication year - 2019
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14742
Subject(s) - fucosylation , apoptosis , receptor , fucosyltransferase , cancer research , tumor necrosis factor alpha , biology , glycosylation , programmed cell death , chemistry , microbiology and biotechnology , fucose , immunology , biochemistry , enzyme , glycoprotein
The remarkable pro‐apoptotic properties of tumour necrosis factor ( TNF )‐related apoptosis‐inducing ligand ( TRAIL ) have led to considerable interest in this protein as a potential anticancer therapeutic. However, TRAIL is largely ineffective in inducing apoptosis in certain cancer cells, and the mechanisms underlying this selectivity are unknown. In colon adenocarcinomas, posttranslational modifications including O ‐ and N‐ glycosylation of death receptors were found to correlate with TRAIL ‐induced apoptosis. Additionally, mRNA levels of fucosyltransferase 3 ( FUT 3) and 6 ( FUT 6) were found to be high in the TRAIL ‐sensitive colon adenocarcinoma cell line COLO 205. In this study, we use agonistic receptor‐specific TRAIL variants to dissect the contribution of FUT 3 and FUT 6‐mediated fucosylation to TRAIL ‐induced apoptosis via its two death receptors, DR 4 and DR 5. Triggering of apoptosis by TRAIL revealed that the low FUT 3/6‐expressing cells DLD ‐1 and HCT 116 are insensitive to DR 5 but not to DR 4‐mediated apoptosis. By contrast, efficient apoptosis is mediated via both receptors in high FUT 3/6‐expressing COLO 205 cells. The reconstitution of FUT 3/6 expression in DR 5‐resistant cells completely restored TRAIL sensitivity via this receptor, while only marginally enhancing apoptosis via DR 4 at lower TRAIL concentrations. Interestingly, we observed that induction of the salvage pathway by external administration of l ‐fucose restores DR 5‐mediated apoptosis in both DLD ‐1 and HCT 116 cells. Finally, we show that fucosylation influences the ligand‐independent receptor association that leads to increased death inducing signalling complex ( DISC ) formation and caspase‐8 activation. Taken together, these results provide evidence for the differential impact of fucosylation on signalling via DR 4 or DR 5. These findings provide novel opportunities to enhance TRAIL sensitivity in colon adenocarcinoma cells that are highly resistant to DR 5‐mediated apoptosis.