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

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.

Tax is Involved in Up-regulation of HMGB1 Expression Levels by Interaction with C/EBP

“…Generally, HMGB1 is expressed at a basal level as an architectural chromatin-binding protein, but at a slightly elevated level via passive release from damaged or necrotic cells (Beyer et al, 2012;Yi et al, 2013) or active secretion (Akirav et al, 2012;Kang et al, 2013;Mohammad et al, 2013). Moreover, overexpression of HMGB1 protein is observed in breast, colon, and gastrointestinal cancers, as well as in leukemia and other diseases (Kostova et al, 2010;Ohmori et al, 2011;Jube et al, 2012;Lee et al, 2012;Liu et al, 2012;Xing et al, 2012;Yu et al, 2012;Stoetzer et al, 2013).…”

“…In the nucleus, HMGB1 functions as a non-histone nucleosomal protein that binds DNA, contributes to stabilization of nucleosomes, and promotes DNA repair and replication (Bustin, 1999). In the extracellular milieu, HMGB1 is a pro-inflammatory cytokine that acts as an alarmin via passive release from damaged or necrotic cells (Beyer et al, 2012;He et al, 2012;Yi et al, 2013) or by active secretion from innate immune system cells in response to LPS, TNF-a or IL-1β stimulation to induce T-cell activation, cytokine production, and inflammatory responses by the transduction of cellular signals through its receptors (Akirav et al, 2012;Kang et al, 2013;Mohammad et al, 2013). Aside from these pro-inflammatory functions, HMGB1 protein also promotes regeneration processes and accelerates cell cycle progression.…”

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

“…35,36 In the cytoplasm, HMGBs bind immunogenic nucleotides and deliver them to the cytosolic nucleic acid sensors retinoic acid-inducible gene I, MDA5, AIM2 and DAI and to the endosome nucleic acid-sensing TLRs (TLR3, TLR7 and TLR9). 7,10 Reports have also highlighted the interactions of HMGB1 with TLR9, retinoic acid-inducible gene I and TIM-3 10,37,38 and the vital role of HMGBs in autophagy regulation, 39 mitochondrial function and morphology [40][41][42] and cell proliferation. [43][44][45] Comparatively, an understanding of HMGBs in the nucleus is limited.…”

Paradoxical Role of HMGB1 in Pancreatic Cancer: Tumor Suppressor or Tumor Promoter?

“…Moreover, RAGE and HMGB1 jointly enhance tumor cell mitochondrial complex I activity and, therefore, ATP production, needed for supporting anabolism and tumor cell proliferation and migration (4).…”

“…Through a signaling pathway involving the receptor for advanced glycation end products (RAGE), HMGB1 has been associated with tumor progression due to its elevated expression in certain cancer types, especially pancreatic cancer (3). Likewise, HMGB1 has been correlated to invasion and metastasis (4), resistance to chemotherapy agents (5,6) and autophagy and immunogenic cell death (7).…”