MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies.

Abstract	KRAS mutation, which occurs in ∼ 95% of pancreatic ductal adenocarcinoma (PDA), has been shown to program tumor metabolism. MCT4 is highly upregulated in a subset of PDA with a glycolytic gene expression program and poor survival. Models with high levels of MCT4 preferentially employ glycolytic metabolism. Selectively in such "addicted" models, MCT4 attenuation compromised glycolytic flux with compensatory induction of oxidative phosphorylation and scavenging of metabolites by macropinocytosis and autophagy. In spite of these adaptations, MCT4 depletion induced cell death characterized by elevated reactive oxygen species and metabolic crisis. Cell death induced by MCT4-depletion was augmented by inhibition of compensatory pathways. In xenograft models, MCT4 had a significant impact on tumor metabolism and was required for rapid tumor growth. Together, these findings illustrate the metabolic diversity of PDA described by MCT4, delineate pathways through which this lactate transporter supports cancer growth, and demonstrate that PDA can be rationally targeted based on metabolic addictions.
Authors	GuemHee Baek, Yan F Tse, Zeping Hu, Derek Cox, Noah Buboltz, Peter McCue, Charles J Yeo, Michael A White, Ralph J DeBerardinis, Erik S Knudsen, Agnieszka K Witkiewicz
Journal	Cell reports (Cell Rep) Vol. 9 Issue 6 Pg. 2233-49 (Dec 24 2014) ISSN: 2211-1247 [Electronic] United States
PMID	25497091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright	Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
Chemical References	Biomarkers, Tumor Monocarboxylic Acid Transporters Muscle Proteins Reactive Oxygen Species SLC16A4 protein, human
Topics	Animals Biomarkers, Tumor (genetics, metabolism) Carcinoma, Pancreatic Ductal (metabolism, pathology) Cell Death Cell Line, Tumor Glycolysis Humans Mice Monocarboxylic Acid Transporters (genetics, metabolism) Muscle Proteins (genetics, metabolism) Oxidative Phosphorylation Pancreatic Neoplasms (metabolism, pathology) Prognosis Reactive Oxygen Species (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!