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

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.

Blocking ATM Attenuates SKOV3 Cell Proliferation and Migration by Disturbing OGT/OGA Expression via hsa-miR-542-5p

“…ATM inhibitor KU60019, OGT inhibitor OSMI-1 and OGA inhibitor MK-8719 were purchased from tsbiochem (tsbiochem, ShangHai, CN), and stored at -80°C in stock solution (KU60019 and MK-8719,10 mM; OSMI-1, 20mM, dissolved with dimethylsulfoxide). Then, 5 × 10 5 cells/ml SKOV3 cells were collected during their logarithmic phases of growth and treated with 10 μM KU60019 ( 21 ) or MK-8719 ( 22 ), or 20 μM OSMI-1 ( 23 ) for 24 h.…”

Targeting O-GlcNAcylation to overcome resistance to anti-cancer therapies

“…It was recently demonstrated that EGFR is directly O -GlcNAcylated and that OGT knock-down downregulates EGFR and its downstream PI3K/AKT pathway, and promotes cell cycle arrest and apoptosis in 786-O renal cell carcinoma cells ( 111 ). Pending further investigations to determine whether hypo- O -GlcNAcylation induced by PGM3 inhibition is directly involved in GEM sensitization mechanism, we speculate that hypo- O -GlcNAcylation could activate CHOP by inducing ROS accumulation, ER stress, and UPR activation ( 73 , 74 ) ( Figure 2 ). Therapeutic approaches involving PGM3 inhibition, and possibly inhibition of protein O -GlcNAcylation, in combination with GEM could be promising to bypass the drug resistance in pancreatic cancer.…”

“…Recently, Lee et al. (2021) demonstrate that a combination of TRAIL and OSMI-1 (OGT inhibitor) enhances TRAIL-induced apoptosis in colon cancer cells and xenograft tumors by lowering the activity of Inhibitory κB Kinase β (IKKβ) and inhibition of downstream NF-κB pro-survival signaling ( 73 ) ( Figure 1 ). Additionally, OGT inhibition by OSMI-1 improves TRAIL-induced apoptosis by a parallel mechanism involving ER stress response.…”

“…Hypo- O -GlcNAcylation induces the accumulation of reactive oxygen species (ROS) that leads to ER stress and activation of UPR signaling pathways including Protein Kinase RNA (PKR)-like kinase (PERK). Activation of PERK enhances expression of the pro-apoptotic protein C/EBP Homologous Protein (CHOP) that, in turn, up-regulates expression of TRAIL-R2 leading to TRAIL sensitization ( 73 ) ( Figure 1 ). Concordantly, O -GlcNAcylation prevents activation of CHOP ( 74 ).…”

“…Despite being membrane permeable and relatively large, having low aqueous solubility and inducing toxicity limiting its activity in cellulo ( 140 ), OSMI-1 could still have therapeutic potential since it synergistically enhances some cancer therapies ( i.e. TRAIL and DOX)-induced apoptosis in vivo in tumor xenograft models ( 73 , 113 ). The aminothiazoline derivative Thiamet-G is the most widely used OGA inhibitor in vitro and in vivo due to its stability, selectivity, oral bioavailability, and ability to cross the blood-brain barrier ( 141 ).…”