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

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

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)567-577
Number of pages11
JournalOncogene
Volume33
Issue number5
DOIs
StatePublished - Jan 30 2014
Externally publishedYes

Keywords

  • ATP
  • HMGB1
  • RAGE
  • inflammation
  • mitochondria
  • pancreatic cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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