Differential regulation of ZEB1 and EMT by MAPK-interacting protein kinases (MNK) and eIF4E in pancreatic cancer

Human pancreatic ductal adenocarcinoma (PDAC) tumors are associated with dysregulation of mRNA translation. In this report, it is demonstrated that PDAC cells grown in collagen exhibit increased activation of the MAPK-interacting protein kinases (MNK) that mediate eIF4E phosphorylation. Pharmacologic and genetic targeting of MNKs reverse epithelial-mesenchymal transition (EMT), decrease cell migration, and reduce protein expression of the EMT-regulator ZEB1 without affecting ZEB1 mRNA levels. Paradoxically, targeting eIF4E, the bestcharacterized effector of MNKs, increases ZEB1 mRNA expression through repression of ZEB1-targeting miRNAs, miR-200c andmiR-141. In contrast, targeting theMNK effector hnRNPA1, which can function as a translational repressor, increases ZEB1 protein without increasing ZEB1 mRNA levels. Importantly, treatment with MNK inhibitors blocks growth of chemoresistant PDAC cells in collagen and decreases the number of aldehyde dehydrogenase activity-positive (Aldefluor+) cells. Significantly, MNK inhibitors increase E-cadherin mRNA levels and decrease vimentin mRNA levels in human PDAC organoids without affecting ZEB1 mRNA levels. Importantly, MNK inhibitors also decrease growth of human PDAC organoids. Implications: These results demonstrate differential regulation of ZEB1 and EMT by MNKs and eIF4E, and identify MNKs as potential targets in pancreatic cancer.