Abstract B96: The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics.

Background and Aims: Recently altered cellular bioenergetics and inflammation have been added to the list of essential hallmarks of cancer. The precise mechanisms regulating these processes are not well characterized. We previously observed that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), promote early pancreatic carcinogenesis through an IL-6/STAT3-dependent pathway. Based on previous data suggesting a role for IL-6/STAT3 in mitochondrial function, we hypothesized that the RAGE/HMGB1 axis would play a role pancreatic tumor cell mitochondrial bioenergetics.

Methods: The effects of HMGB1/RAGE on ATP generation were studied in cultured human and murine pancreatic tumor cell lines in vitro utilizing targeted knockdown with shRNA and site specific mutagenesis. Observations were confirmed in vivo utilizing orthotopic transplantation models of pancreatic cancer derived from RAGE wild-type or knockdown cell lines.

Results: We found RAGE in the mitochondria of cultured tumor cells, as well as primary human tumor explants. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. There is a direct interaction between RAGE and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). The mitochondrial localization signal Ser377 of RAGE is phosphorylated by ERK1/2, which is required for HMGB1-mediated RAGE activation within the mitochondria. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo.

Conclusions: These findings link the HMGB1-RAGE pathway with changes in cellular bioenergetics. Moreover, our observations provide a novel mechanism by which necrosis and inflammation, within the tumor microenvironment, can promote tumor progression.

Note: This abstract was not presented at the conference.

Citation Format: Rui Kang, Daolin Tang, Nicole E. Schapiro, Michael T. Lotze, Herbert J. Zeh. The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B96.