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.