Journal Article

The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics

Wang, H, Loux, T, Schapiro, N E, Zeh, H J, Tang, D, Van Houten, B, Kang, R, Lotze, M T, Livesey, K M, Billiar, T R

2014

Overview

Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo . These findings link, for the first time, the HMGB1–RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/57/1464 / 631/67/395 / 631/80/86 / 692/699/67/1504/1713 / Adenosine triphosphatase / Adenosine triphosphate / Adenosine Triphosphate - biosynthesis / Adenosine Triphosphate - metabolism / Angiogenesis / Animals / Apoptosis / Butadienes - pharmacology / Cancer / Cancer cells / CD24 Antigen - genetics / Cell Biology / Cell Line, Tumor / Cell Movement / Cell Proliferation / Cycloheximide - pharmacology / Development and progression / Electron Transport Complex I - antagonists & inhibitors / Electron Transport Complex I - metabolism / Energy Metabolism / Enzyme Inhibitors - pharmacology / Extracellular Signal-Regulated MAP Kinases - drug effects / Extracellular Signal-Regulated MAP Kinases - metabolism / Growth / HMGB1 Protein - drug effects / HMGB1 Protein - metabolism / Human Genetics / Humans / Inflammation / Inflammation - metabolism / Internal Medicine / MAP Kinase Kinase 2 - genetics / MAP Kinase Kinase 2 - metabolism / Medicine / Medicine & Public Health / Mice / Mitochondria / Mitochondria - drug effects / Mitochondria - metabolism / Muscle proteins / Necrosis / NF-kappa B - drug effects / NF-kappa B - metabolism / Nitriles - pharmacology / Oncology / Oncology, Experimental / original-article / Pancreatic cancer / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Phosphorylation - drug effects / Physiological aspects / Protein Binding - drug effects / Protein Synthesis Inhibitors - pharmacology / Receptor for Advanced Glycation End Products - genetics / Receptor for Advanced Glycation End Products - metabolism / RNA Interference / RNA, Small Interfering - genetics / Rotenone - pharmacology / Signal Transduction / Studies / Toll-Like Receptor 2 - genetics / Toll-Like Receptor 4 - genetics / Tumor Microenvironment / Uncoupling Agents