TY - JOUR
T1 - Differential regulation of ZEB1 and EMT by MAPK-interacting protein kinases (MNK) and eIF4E in pancreatic cancer
AU - Kumar, Krishan
AU - Chow, Christina R.
AU - Ebine, Kazumi
AU - Arslan, Ahmet D.
AU - Kwok, Benjamin
AU - Bentrem, David J.
AU - Eckerdt, Frank D.
AU - Platanias, Leonidas C.
AU - Munshi, Hidayatullah G.
N1 - Funding Information:
This work was supported by grant R01CA186885 (to H.G. Munshi) and R01CA121192 and R01CA155566 (to L.C. Platanias) from the NCI and Merit awards I01BX001363 (to H.G. Munshi) and I01CX000916 (to L.C. Platanias) from the Department of Veterans Affairs. This work was also supported by the training grant T32CA070085 (to C.R. Chow and A.D. Arslan) from the NCI. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/2
Y1 - 2016/2
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-15-0285
DO - 10.1158/1541-7786.MCR-15-0285
M3 - Article
C2 - 26609108
AN - SCOPUS:84958151465
SN - 1541-7786
VL - 14
SP - 216
EP - 227
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
IS - 2
ER -