Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis and preferentially kills tumor cells by engaging specific glycosylated death receptors, resulting in the internalization of ligand/receptor complexes and recruitment of the initiator caspase-8 to an activation platform known as the death-inducing signaling complex (DISC). However, emergence of TRAIL-resistant sub-populations may contribute to therapeutic failure. To investigate resistance mechanisms, we isolated a stable TRAIL-resistant sub-population of the metastatic colon cancer cell line LS-LIM6, designated LIM6-TR. LIM6-TR cells are impaired in endocytosis of TRAIL/death receptors complexes and failed to recruit/activate caspase-8 to the DISC upon TRAIL stimulation. Differential activation of Wnt and JNK pathways is not responsible for acquisition of TRAIL resistance. LIM6-TR cells display a marked increase in cell-surface expression of galectin-3, an endogenous lectin, which co-localizes with and binds death receptors. Silencing of galectin-3 restores TRAIL sensitivity and promotes TRAIL-mediated endocytosis of TRAIL/death receptors complexes. Inhibitors of galectin-3 and glycosylation also re-sensitize LIM6-TR to TRAIL and restore internalization of ligand/receptors complexes. These studies identify a novel TRAIL-resistance mechanism in which galectin-3 impedes trafficking of death receptor by anchoring them in glycan nano-clusters, blocking the execution of the apoptosis signal.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology
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Apoptosis / drug effects
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Apoptosis / genetics
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Caspase 8 / genetics
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Caspase 8 / metabolism
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Cell Line, Tumor
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology
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Death Domain Receptor Signaling Adaptor Proteins / genetics
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Death Domain Receptor Signaling Adaptor Proteins / metabolism
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Galectin 3 / genetics
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Galectin 3 / metabolism*
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Gene Silencing
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Glycosylation / drug effects
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Humans
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Protein Transport / drug effects
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Protein Transport / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
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Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
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TNF-Related Apoptosis-Inducing Ligand / genetics
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TNF-Related Apoptosis-Inducing Ligand / metabolism
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TNF-Related Apoptosis-Inducing Ligand / pharmacology*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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Wnt Signaling Pathway / drug effects
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Wnt Signaling Pathway / genetics
Substances
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Death Domain Receptor Signaling Adaptor Proteins
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Galectin 3
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Neoplasm Proteins
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Wnt Proteins
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MAP Kinase Kinase 4
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Caspase 8