title: Differential Regulation of ZEB1 and EMT by MAPK-Interacting Protein Kinases (MNK) and eIF4E in Pancreatic Cancer.
abstract: 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 best-characterized effector of MNKs, increases ZEB1 mRNA expression through repression of ZEB1-targeting miRNAs, miR-200c and miR-141. In contrast, targeting the MNK 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.
  
  
  CONCLUSIONS
  These results demonstrate differential regulation of ZEB1 and EMT by MNKs and eIF4E, and identify MNKs as potential targets in pancreatic cancer.
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Jesse Brown VA Medical Center, Chicago, Illinois.
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Chow
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Jesse Brown VA Medical Center, Chicago, Illinois.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ebine
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Ahmet D
authors.initials: AD
authors.lastname: Arslan
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kwok
authors.affiliation: Jesse Brown VA Medical Center, Chicago, Illinois. The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.affiliation: The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Frank D
authors.initials: FD
authors.lastname: Eckerdt
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Jesse Brown VA Medical Center, Chicago, Illinois. The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. Jesse Brown VA Medical Center, Chicago, Illinois. The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois. h-munshi@northwestern.edu.
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D039561:Eukaryotic Initiation Factor-4E; D018398:Homeodomain Proteins; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D017346:Protein Serine-Threonine Kinases