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

Oncogene volume 33, pages 567–577 (2014)Cite this article

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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.

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Acknowledgements

We dedicate this manuscript to the memory of Angelika Bierhaus, PhD, our friend and benefactor. She was a pioneering RAGE biologist, generous and kind in her dealings with colleagues, who provided us the mice with which we completed this work, and who sadly passed away on 15 April 2012 after a long and courageous battle with cancer. Angelika had a great love of life and she was generous, kind and warm hearted. She was always full of plans for scientific endeavors, even when her disease began to take its toll. She steadfastly denied that she would be defeated, recently celebrating her 50th birthday; however, she was aware that her remaining time was short. She dedicated herself to research, but despite her incredible strength, she was not able to overcome the disease, which tragically took her life.We thank Christine Heiner (University of Pittsburgh. Department of Surgery) for her critical reading of the manuscript. This project was supported by grants from the National Institutes of Health (P01 CA 101944 to MTL, R01CA160417 to DT) and the University of Pittsburgh (DT and HJZ). This project used University of Pittsburgh Cancer Institute shared resources that are supported in part by award P30CA047904. We also thank Dr Donna Stolz and Simon Watkins for providing the confocal microscopy facilities at the Center for Biologic Imaging at University of Pittsburgh School of Medicine.

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Authors and Affiliations

  1. Department of Surgery, Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    R Kang, D Tang, N E Schapiro, T Loux, K M Livesey, T R Billiar, M T Lotze & H J Zeh

  2. North Shore University Hospital, New York University School of Medicine, Manhasset, NY, USA

    H Wang

  3. Laboratory of Molecular and Cell Biology Program, Hillman Cancer Center, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    B Van Houten

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  1. R Kang
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Correspondence to D Tang, M T Lotze or H J Zeh.

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Kang, R., Tang, D., Schapiro, N. et al. The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. Oncogene 33, 567–577 (2014). https://doi.org/10.1038/onc.2012.631

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