Glucose Metabolism Reprogrammed by Overexpression of IKK? Promotes Pancreatic Tumor Growth.

ABSTRACT: Aberrant expression of the kinase IKK? in pancreatic ductal adenocarcinoma (PDAC) has been associated with poor prognosis. In this study, we define a pathobiologic function for IKK? in reprogramming glucose metabolism and driving progression in PDAC. Silencing IKK? 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. IKK? silencing also attenuated c-Myc in a manner associated with diminished signaling through an AKT/GSK3?/c-MYC phosphorylation cascade that promoted MYC nuclear accumulation. In an orthotopic mouse model, IKK?-silenced PDAC exhibited a relative reduction in glucose uptake, tumorigenicity, and metastasis. Overall, our findings offer a preclinical mechanistic rationale to target IKK? to improve the therapeutic management of PDAC in patients. Cancer Res; 76(24); 7254-64. ©2016 AACR.

SUBMITTER: Zubair H 

PROVIDER: S-EPMC5161695 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature