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PMID: 23318458 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

Oncogene ·Vol. 33 ·No. 5 ·2014-01-30 ·Pages 567-77

Kang R, Tang D, Schapiro NE, Loux T, Livesey KM, Billiar TR, Wang H, Van Houten B, Lotze MT, Zeh HJ

Abstract

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.

MeSH Terms
Adenosine Triphosphate/biosynthesis,metabolism Animals Butadienes/pharmacology CD24 Antigen/genetics Cell Line, Tumor Cell Movement Cell Proliferation Cycloheximide/pharmacology Electron Transport Complex I/antagonists & inhibitors,metabolism Energy Metabolism Enzyme Inhibitors/pharmacology Extracellular Signal-Regulated MAP Kinases/drug effects,metabolism HMGB1 Protein/drug effects,metabolism Humans Inflammation/metabolism MAP Kinase Kinase 2/genetics,metabolism Mice Mitochondria/drug effects,metabolism NF-kappa B/drug effects,metabolism Nitriles/pharmacology Pancreatic Neoplasms/metabolism,pathology Phosphorylation/drug effects Protein Binding/drug effects Protein Synthesis Inhibitors/pharmacology RNA Interference RNA, Small Interfering/genetics Receptor for Advanced Glycation End Products/genetics,metabolism Rotenone/pharmacology Signal Transduction Toll-Like Receptor 2/genetics Toll-Like Receptor 4/genetics Tumor Microenvironment Uncoupling Agents
Chemicals
Butadienes CD24 Antigen Cd24a protein, mouse Enzyme Inhibitors HMGB1 Protein HMGB1 protein, human NF-kappa B Nitriles Protein Synthesis Inhibitors RNA, Small Interfering Receptor for Advanced Glycation End Products Tlr2 protein, mouse Tlr4 protein, mouse Toll-Like Receptor 2 Toll-Like Receptor 4 U 0126 Uncoupling Agents Rotenone Adenosine Triphosphate Cycloheximide Extracellular Signal-Regulated MAP Kinases MAP Kinase Kinase 2 Map2k2 protein, mouse Electron Transport Complex I
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Kang R
Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Tang D
Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Schapiro N E
Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Loux T
Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Livesey K M
Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Billiar T R
Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Wang H
North Shore University Hospital, New York University School of Medicine, Manhasset, NY, USA.
Van Houten B
Laboratory of Molecular and Cell Biology Program, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.
Lotze M T
Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Zeh H J
Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/onc.2012.631
Published
2014-01-30
Epub
2013-00-14
Pages
567-77
Language
English
Region
England
NLM ID
8711562
PMCID
PMC3795800
Subset
IM
Grants
NCI NIH HHS · P01 CA101944 · United States
NCI NIH HHS · P30 CA047904 · United States
NCI NIH HHS · R01CA160417 · United States
NCI NIH HHS · P01 CA 101944 · United States
NCI NIH HHS · P30CA047904 · United States
NCI NIH HHS · R01 CA160417 · United States
External Links
PubMed source DOI: 10.1038/onc.2012.631 PMC Full Text View journal details
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