Inhibition of MUC1 biosynthesis via threonyl-tRNA synthetase suppresses pancreatic cancer cell migration

Seung Jae Jeong,Hee-sun Moon,Dong Ki Lee,Ina Yoon,Jong Hyun Kim,Doyeun Kim,Ji-Ae Song,Beom Jin Lim,Sunghoon Kim

doi:10.1038/emm.2017.231

Abstract

Mucin1 (MUC1), a heterodimeric oncoprotein, containing tandem repeat structures with a high proportion of threonine, is aberrantly overexpressed in many human cancers including pancreatic cancer. Since the overall survival rate of pancreatic cancer patients has remained low for several decades, novel therapeutic approaches are highly needed. Intestinal mucin has been known to be affected by dietary threonine supply since de novo synthesis of mucin proteins is sensitive to luminal threonine concentration. However, it is unknown whether biosynthesis of MUC1 is regulated by threonine in human cancers. In this study, data provided suggests that threonine starvation reduces the level of MUC1 and inhibits the migration of MUC1-expressing pancreatic cancer cells. Interestingly, knockdown of threonyl-tRNA synthetase (TRS), an enzyme that catalyzes the ligation of threonine to its cognate tRNA, also suppresses MUC1 levels but not mRNA levels. The inhibitors of TRS decrease the level of MUC1 protein and prohibit the migration of MUC1-expressing pancreatic cancer cells. In addition, a positive correlation between TRS and MUC1 levels is observed in human pancreatic cancer cells. Concurrent with these results, the bioinformatics data indicate that co-expression of both TRS and MUC1 is correlated with the poor survival of pancreatic cancer patients. Taken together, these findings suggest a role for TRS in controlling MUC1-mediated cancer cell migration and provide insight into targeting TRS as a novel therapeutic approach to pancreatic cancer treatment.

Highlights

Pancreatic cancer is one of the most aggressive human cancers
Threonine deprivation reduces MUC1 levels in pancreatic cancer cells Since previous reports have shown that de novo synthesis of mucin is sensitive to threonine concentration,[13,14,15,16,17] we hypothesized that MUC1 would be affected by threonine levels in pancreatic cancer cells
When Panc 10.05 cells were incubated in threonine-free media, cellular levels of MUC1 and MUC1-CT were reduced in a timedependent manner (Figure 1c) but mRNA levels of MUC1 were not changed under the same conditions (Figure 1d)

Summary

Introduction

Pancreatic cancer is one of the most aggressive human cancers. MUC1, a member of the mucin family and a heterogeneous glycoprotein, is normally expressed at the apical surface of polarized epithelial cells of the mammary gland, stomach, duodenum, pancreas, uterus, prostate and lungs.[4] In malignancy, MUC1 is overexpressed and repositioned over the entire cell membrane of carcinoma cells and contributes to neoplastic transformation, tumor survival, angiogenesis, and metastasis.[5] the cytoplasmic tail of MUC1 (MUC1-CT) mediates intracellular signaling functions associated with cancer cell survival and metastasis.[6] Aberrant overexpression of MUC1 is found in most human carcinomas including pancreatic cancer[7] and often used as a diagnostic marker for metastatic progression.[8]

Methods

Results

Conclusion