• Anticancer research · Jul 2016

    Enhanced TLR4 Expression on Colon Cancer Cells After Chemotherapy Promotes Cell Survival and Epithelial-Mesenchymal Transition Through Phosphorylation of GSK3β.

    • Yoon Hee Chung and Daejin Kim.
    • Department of Anatomy, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
    • Anticancer Res. 2016 Jul 1; 36 (7): 3383-94.

    BackgroundPhosphorylation of glycogen synthase kinase 3β (GSK3β) by phosphatidyl-inositide 3-kinase (PI3K)/protein kinase B (AKT) or inhibition of GSK3β with small-molecule inhibitor attenuates cell survival and proliferation and increases apoptosis in most cancer cell lines. In this study, we investigated the role of phosphorylated GSK3β activated by enhanced toll-like receptor 4 (TLR4) expression in drug-treated colon cancer cells as a model of post-chemotherapy cancer cells.Materials And MethodsThe effect of TLR4 stimulation on metastasis and apoptosis in drug-exposed colon cancer cells was determined by real-time polymerase chain reaction (PCR) and immunoblotting.ResultsDespite the induction of apoptosis after treatment with oxaliplatin and 5-fluorouracil, lipopolysaccharide (LPS) stimulation via increased TLR4 in drug-treated cancer cells effectively inhibited apoptosis through up-regulation of expression of anti-apoptosis-related B-cell lymphoma 2 (BCL2) family proteins [X-linked inhibitor of apoptosis protein (XIAP), BCL2, and survivin] and drug-resistance proteins [multidrug-resistance protein 1 (MDR1), multidrug resistance-associated protein (MRP)1/2/3]. LPS-mediated signaling in drug-treated cancer cells elevated the expression of phosphorylated GSK3β, extracellular signal-regulated kinase (ERK), and the p65 subunit of nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB). Pharmacological inhibition of GSK3β (using SB216763) reduced phosphorylation of GSK3β, re-activated caspase-dependent apoptosis, and blocked the expression of cancer stem cell markers and invasive characteristics in LPS-stimulated drug-treated cells. In addition, the ERK-specific inhibitor, PD98059, triggered the apoptosis of TLR4-activated drug-exposed colon cancer cells, whereas there was no effect on the expression of epithelial-mesenchymal transition markers or GSK3β phosphorylation.ConclusionThese results suggest that TLR4-induced GSK3β and ERK phosphorylation independently controls cancer cell survival and regulation of GSK3β and ERK after chemotherapy, making TLR4 a critical target for reducing drug resistance and metastasis in patients with colon cancer.Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

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