title: Glucose Metabolism Reprogrammed by Overexpression of IKKε Promotes Pancreatic Tumor Growth.
abstract: Aberrant expression of the kinase IKKε in pancreatic ductal adenocarcinoma (PDAC) has been associated with poor prognosis. In this study, we define a pathobiologic function for IKKε in reprogramming glucose metabolism and driving progression in PDAC. Silencing IKKε in PDAC cells, which overexpressed it endogenously, was sufficient to reduce malignant cell growth, clonogenic potential, glucose consumption, lactate secretion, and expression of genes involved in glucose metabolism, without impacting the basal oxygen consumption rate. IKKε silencing also attenuated c-Myc in a manner associated with diminished signaling through an AKT/GSK3β/c-MYC phosphorylation cascade that promoted MYC nuclear accumulation. In an orthotopic mouse model, IKKε-silenced PDAC exhibited a relative reduction in glucose uptake, tumorigenicity, and metastasis. Overall, our findings offer a preclinical mechanistic rationale to target IKKε to improve the therapeutic management of PDAC in patients. Cancer Res; 76(24); 7254-64. ©2016 AACR.
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Haseeb
authors.initials: H
authors.lastname: Zubair
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Shafquat
authors.initials: S
authors.lastname: Azim
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Sanjeev Kumar
authors.initials: SK
authors.lastname: Srivastava
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Arun
authors.initials: A
authors.lastname: Bhardwaj
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Mohammad Aslam
authors.initials: MA
authors.lastname: Khan
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Girijesh Kumar
authors.initials: GK
authors.lastname: Patel
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.
authors.forename: Sumit
authors.initials: S
authors.lastname: Arora
authors.affiliation: Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: James Elliot
authors.initials: JE
authors.lastname: Carter
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.|Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Seema
authors.initials: S
authors.lastname: Singh
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama. asingh@health.southalabama.edu.|Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama.
authors.forename: Ajay Pratap
authors.initials: AP
authors.lastname: Singh
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051550:I-kappa B Kinase / Q000096:biosynthesis*; D015151:Immunoblotting; D047468:Immunoprecipitation; D051379:Mice; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D051550:I-kappa B Kinase; D005947:Glucose