Abstract

BackgroundColorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 heterodimeric protein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. Here, we investigate the effects of the MUC1-C subunit inhibitor (GO-203), which disrupts MUC1-C homo-oligomerization, on human colorectal cancer cells.MethodsTIGAR mRNA level was determined using qRT-PCR. Western blotting was used to measure TIGAR protein level and AKT-mTOR-S6K1 pathways. Reactive oxygen species and apoptosis were measured by flow cytometry. Effect of MUC1-C peptide, GO-203 was studied on colorectal xenograft tumors. Immunohistochemistry was utilized for TIGAR staining.ResultsTreatment of MUC1-overexpressing SKCO-1 and Colo-205 colon cancer cells with GO-203 was associated with downregulation of the TP53-inducible glycolysis and apoptosis regulator (TIGAR) protein. TIGAR promotes the shunting of glycolytic intermediates into the pentose phosphate pathway and thus is of importance for maintaining redox balance. We show that GO-203-induced suppression of TIGAR is mediated by inhibition of AKT and the downstream mTOR pathway. The results also demonstrate that targeting MUC1-C blocks eIF4A cap-dependent translation of TIGAR. In concert with these results, GO-203-induced suppression of TIGAR was associated with decreases in GSH levels. GO-203 treatment also resulted in increases in reactive oxygen species (ROS) and loss of mitochondrial transmembrane potential. Consistent with these results, GO-203 inhibited the growth of colon cancer cells in vitro and as xenografts in nude mice. Inhibition of MUC1-C also downregulated TIGAR expression in xenograft tissues.ConclusionsThese findings indicate that MUC1-C is a potential target for the treatment of colorectal cancer. Colorectal cancer patients who overexpress MUC1-C may be candidates for treatment with the MUC1-C inhibitor alone or in combination therapy with other agents.

Highlights

  • Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death

  • The present study demonstrates that treatment of human colorectal cancer cell lines with the MUC1 C-terminal subunit (MUC1-C) inhibitor GO-203 is associated with downregulation of the AKT→mTOR pathway and suppression of cap-dependent translation of the TP53-inducible glycolysis and apoptosis regulator (TIGAR) (TP53-induced glycolysis and apoptosis regulator) protein

  • To determine whether the AKT-mTORC-S6 kinases (S6Ks) pathway is involved in TIGAR protein translation, SKCO1 cells were treated with PI3K inhibitor, LY294002 and Akt inhibitor, GSK690693

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Summary

Introduction

Colorectal cancer is third most common malignancy and is the second most common cause of cancer-related death. The MUC1 heterodimeric protein is aberrantly overexpressed in colorectal cancer and has been linked to poor outcomes in this disease. Colorectal cancer (CRC) is the third most common cancer in the world. CRC is the fourth leading cause of cancer-related mortality, causing over 600,000 deaths per year. Colorectal cancer is the most common cancer in 40 European countries [1]. Ahmad et al Molecular Cancer (2017) 16:33 is regulated by Wnt signaling. Mutations in APC and β-catenin are among the earlier events that lead to hyperplasia in the intestinal crypts leading to colorectal cancer development [4, 5]. Wnt signaling is required for colorectal cancer progression and metastasis [6]

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