OSMI-1 Enhances TRAIL-Induced Apoptosis through ER Stress and NF-κB Signaling in Colon Cancer Cells.

Su-Jin Lee,Da-Eun Lee,Oh-Shin Kwon,Soo-Young Choi

doi:10.3390/ijms222011073

Abstract

Levels of O-GlcNAc transferase (OGT) and hyper-O-GlcNAcylation expression levels are associated with cancer pathogenesis. This study aimed to find conditions that maximize the therapeutic effect of cancer and minimize tissue damage by combining an OGT inhibitor (OSMI-1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). We found that OSMI-1 treatment in HCT116 human colon cancer cells has a potent synergistic effect on TRAIL-induced apoptosis signaling. Interestingly, OSMI-1 significantly increased TRAIL-mediated apoptosis by increasing the expression of the cell surface receptor DR5. ROS-induced endoplasmic reticulum (ER) stress by OSMI-1 not only upregulated CHOP-DR5 signaling but also activated Jun-N-terminal kinase (JNK), resulting in a decrease in Bcl2 and the release of cytochrome c from mitochondria. TRAIL induced the activation of NF-κB and played a role in resistance as an antiapoptotic factor. During this process, O-GlcNAcylation of IκB kinase (IKK) and IκBα degradation occurred, followed by translocation of p65 into the nucleus. However, combination treatment with OSMI-1 counteracted the effect of TRAIL-mediated NF-κB signaling, resulting in a more synergistic effect on apoptosis. Therefore, the combined treatment of OSMI-1 and TRAIL synergistically increased TRAIL-induced apoptosis through caspase-8 activation. Conclusively, OSMI-1 potentially sensitizes TRAIL-induced cell death in HCT116 cells through the blockade of NF-κB signaling and activation of apoptosis through ER stress response.

Highlights

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a type of cytokine known to induce apoptosis by binding to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R1/DR4 and TRAIL-R2/DR5 [1,2].TRAIL signaling is transmitted to the death-inducing signaling complex (DISC) present in the cell membrane and induces apoptosis by activating caspase-8 [3,4]
We initially investigated the effect of combined OSMI-1 and TRAIL treatment on cell viability in HCT116 and HepG2 cells using the MTT assay
The results indicate that TRAIL-induced apoptosis occurs through the activation of caspase-8, whereas OSMI-1 treatment increases the release of the proapoptotic factor, cytochrome c, resulting from mitochondrial damage

Summary

Introduction

TRAIL signaling is transmitted to the death-inducing signaling complex (DISC) present in the cell membrane and induces apoptosis by activating caspase-8 [3,4]. The extrinsic apoptosis pathway occurs through caspase-8 as it directly activates an effector, such as caspase-3 [5] and caspase-8 can cleave tBid, which interacts with Bax and Bak to induce mitochondrial damage [6,7]. In addition to activating apoptosis, TRAIL can induce nonapoptotic signaling, such as certain survival pathways that may promote resistance against TRAIL. Activation of proinflammatory pathways by TRAIL increases proliferation, migration, invasion and/or metastasis of cancer cells, primarily through nuclear factor-kappa B (NF-κB), PI3K, AKT and MAPK [10,11,12]. Recent studies have confirmed that NF-κB is often constitutively activated in human cancer cells [13]

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