Abstract
Background: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells in cancer patients. However, patients often develop TRAIL resistance; thus, agents that can sensitize cells to TRAIL therapy would be beneficial clinically. Methods: Immunoblotting, flow cytometry, confocal microscopy, qPCR and caspase 8 activity assays were used to investigate whether glucosamine (GlcN) can sensitize cancer cells to TRAIL thereby enhancing apoptosis and potentially improving clinical response. Results: GlcN sensitized DU145 cells to TRAIL-induced apoptosis but did not increase death receptor 5 (DR5) cell surface expression. Once treated, these cells responded to TRAIL-induced apoptosis through both extrinsic and intrinsic apoptotic pathways as evidenced by the cleavage of both caspases 8 and 9. The combination of GlcN and TRAIL suppressed the expression of key anti-apoptotic factors cFLIP, BCL-XL, MCL-1 and XIAP and translocated BAK to the mitochondrial outer membrane thereby facilitating cytochrome C and SMAC release. In addition to the activation of apoptotic pathways, TRAIL-mediated inflammatory responses were attenuated by GlcN pretreatment reducing nuclear NF-kB levels and the expression of downstream target genes IL-6 and IL-8. Conclusions: GlcN/TRAIL combination could be a promising strategy for treating cancers by overcoming TRAIL resistance and abrogating TRAIL-induced inflammation.
Highlights
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that triggers apoptosis in cancer cells through activation of death domain-containing TRAIL receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) [1]
Weak responses of human tumors to TRAIL prompted us to search for approaches to increase Weak responses of human tumors to TRAIL prompted us to search for approaches to increase the efficacy of TRAIL therapy [6]
endoplasmic reticulum (ER) stress leads to elevated expression of death receptor 5 (DR5) which stimulates the efficacy of TRAIL therapy [6]
Summary
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family that triggers apoptosis in cancer cells through activation of death domain-containing TRAIL receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) [1]. It was determined that some cancer cells were resistant to TRAIL monotherapy through a variety of mechanisms thereby evading cell death To overcome this resistance, a variety of sensitizing agents have been explored, several of which increased sensitivity of cancer cells to TRAIL-induced apoptosis. Results: GlcN sensitized DU145 cells to TRAIL-induced apoptosis but did not increase death receptor 5 (DR5) cell surface expression. Once treated, these cells responded to TRAIL-induced apoptosis through both extrinsic and intrinsic apoptotic pathways as evidenced by the cleavage of both caspases 8 and 9.
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