Decoding the sweet regulation of apoptosis: the role of glycosylation and galectins in apoptotic signaling pathways

Seyrek, Kamil; Richter, M.; Lavrik, Inna N.

doi:10.1038/s41418-019-0317-6

Cited by 53 publications

(32 citation statements)

References 101 publications

(158 reference statements)

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“…Finally, cells predominantly expressing sialylated and fucosylated T antigen are markedly more invasive in vivo , without other major functional alterations. Building on available literature, we hypothesize that changing the glycosylation of membrane receptors may decisively impact on relevant downstream oncogenic pathways 1,92,93 . We are currently trying to identify common molecular grounds between hypoxic and glucose deprived cells and simple cell models that may account for these observations, which will be decisive to support future targeted therapeutic interventions.…”

Section: Resultsmentioning

confidence: 99%

Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

Peixoto

Freitas

Ferreira

et al. 2021

Preprint

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Bladder cancer constitutes one of the deadliest genitourinary diseases, especially when diagnosed at late stages. These tumours harbour microenvironmental niches characterized by low levels of oxygen (hypoxia) and limited glucose supply due to poor vascularization. However, the synergic contribution of these features to disease development is poorly understood. Here, we demonstrated that cells with distinct histopathological and molecular backgrounds responded similarly to such stimuli. Cancer cells arrested proliferation, significantly increased invasive capacity in vitro and enhanced tolerance to cisplatin-based chemotherapy. Reoxygenation and access to glucose restored basal proliferation and invasion levels without triggering stress-induced apoptosis, denoting significant cellular plasticity in adapting to microenvironmental cues. Whole transcriptomics showed major molecular reprogramming, supporting main functional alterations. Metabolomics evidenced fatty acids β-oxidation as main bioenergetic pathway rather than anaerobic glycolysis generally adopted by hypoxic cells. Joint pathway analysis also suggested relevant alterations in mucin-type O-glycan biosynthesis. Glycomics confirmed a major antagonization of O-glycosylation pathways, leading to simple cell glycophenotypes characterized by the accumulation of immature short-chain O-glycans such as Tn and STn antigens at the cell surface. Glycoengineered models reflecting simple cell glycophenotypes were developed and functional studies in vitro and in vivo showed that Tn and STn overexpression decreased proliferation and promoted chemoresistance, reinforcing their close link with tumour aggressiveness. Collectively, we have demonstrated that hypoxia and glucose deprivation trigger more aggressive cell behaviours, in what appears to be an escape mechanism from microenvironmental stress. We propose that, altered glycosylation may be used to target these subpopulations, paving the way for precision oncology.

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Section: Resultsmentioning

confidence: 99%

Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

Peixoto

Freitas

Ferreira

et al. 2021

Preprint

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“…Indeed, there is evidence that galectin-3 traps TRAIL death receptors in glycan nanoclusters and prevents the TRAIL-induced formation of apoptotic receptor complexes ( Mazurek et al, 2012 ). CD95 is also N- and O-glycosylated ( Seyrek et al, 2019 ). In the case of this death receptor, however, it has been reported that inhibition of glycosylation showed only a minor effect on receptor clustering and cell death induction ( Shatnyeva et al, 2011 ) or that it even enhanced cell death induction ( Charlier et al, 2010 ).…”

Section: Cell Intrinsic Factors Control Tnfr Clustering and Activatiomentioning

confidence: 99%

Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily

Kucka

Wajant

2021

Front. Cell Dev. Biol.

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With the exception of a few signaling incompetent decoy receptors, the receptors of the tumor necrosis factor receptor superfamily (TNFRSF) are signaling competent and engage in signaling pathways resulting in inflammation, proliferation, differentiation, and cell migration and also in cell death induction. TNFRSF receptors (TNFRs) become activated by ligands of the TNF superfamily (TNFSF). TNFSF ligands (TNFLs) occur as trimeric type II transmembrane proteins but often also as soluble ligand trimers released from the membrane-bound form by proteolysis. The signaling competent TNFRs are efficiently activated by the membrane-bound TNFLs. The latter recruit three TNFR molecules, but there is growing evidence that this is not sufficient to trigger all aspects of TNFR signaling; rather, the formed trimeric TNFL–TNFR complexes have to cluster secondarily in the cell-to-cell contact zone for full TNFR activation. With respect to their response to soluble ligand trimers, the signaling competent TNFRs can be subdivided into two groups. TNFRs of one group, designated as category I TNFRs, are robustly activated by soluble ligand trimers. The receptors of a second group (category II TNFRs), however, failed to become properly activated by soluble ligand trimers despite high affinity binding. The limited responsiveness of category II TNFRs to soluble TNFLs can be overcome by physical linkage of two or more soluble ligand trimers or, alternatively, by anchoring the soluble ligand molecules to the cell surface or extracellular matrix. This suggests that category II TNFRs have a limited ability to promote clustering of trimeric TNFL–TNFR complexes outside the context of cell–cell contacts. In this review, we will focus on three aspects on the relevance of receptor oligomerization for TNFR signaling: (i) the structural factors which promote clustering of free and liganded TNFRs, (ii) the signaling pathway specificity of the receptor oligomerization requirement, and (iii) the consequences for the design and development of TNFR agonists.

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“…For this reason, research into the mechanisms which underpin cell death has exploded over the past two decades, and we now have a fair understanding of the prominent molecular processes which regulate apoptosis (75). Glycan changes have been linked to apoptosis since the late 1990s (76)(77)(78)(79)(80), and sialylation (including ST6GAL1 mediated sialylation) has been functionally associated with the programmed cell death of several different cell types (21,(81)(82)(83). The TNF family of death receptors regulate programmed cell death, and include proteins such as DR4, DR5 and FAS.…”

Section: St6gal1 In the Hallmarks Of Cancermentioning

confidence: 99%

ST6GAL1: A key player in cancer (Review)

et al. 2019

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Aberrant glycosylation is a universal feature of cancer cells and there is now overwhelming evidence that glycans can modulate pathways intrinsic to tumour cell biology. Glycans are important in all of the cancer hallmarks and there is a renewed interest in the glycomic profiling of tumours to improve early diagnosis, determine patient prognosis and identify targets for therapeutic intervention. One of the most widely occurring cancer associated changes in glycosylation is abnormal sialylation which is often accompanied by changes in sialyltransferase activity. Several sialyltransferases are implicated in cancer, but in recent years ST6 β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) has become increasingly dominant in the literature. ST6GAL1 catalyses the addition of α2,6-linked sialic acids to terminal N-glycans and can modify glycoproteins and/or glycolipids. ST6GAL1 is upregulated in numerous types of cancer (including pancreatic, prostate, breast and ovarian cancer) and can promote growth, survival and metastasis. The present review discusses ST6GAL in relation to the hallmarks of cancer, and highlights its key role in multiple mechanisms intrinsic to tumour cell biology.

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Decoding the sweet regulation of apoptosis: the role of glycosylation and galectins in apoptotic signaling pathways

Cited by 53 publications

References 101 publications

Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

Metabolomics, Transcriptomics and Functional Glycomics Reveals Bladder Cancer Cells Plasticity and Enhanced Aggressiveness Facing Hypoxia and Glucose Deprivation

Receptor Oligomerization and Its Relevance for Signaling by Receptors of the Tumor Necrosis Factor Receptor Superfamily

ST6GAL1: A key player in cancer (Review)

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