RAGE is essential for oncogenic KRAS-mediated hypoxic signaling in pancreatic cancer

• Published in: Cell death & disease Vol. 5; no. 10; p. e1480
• Main Authors: Kang, R, Hou, W, Zhang, Q, Chen, R, Lee, Y J, Bartlett, D L, Lotze, M T, Tang, D, Zeh, H J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-10-2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/109; 631/250/256; 631/67/1504/1713; 631/80/86; 64/60; 692/420/755; Animals; Antibodies; Autophagy; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immunology; Life Sciences; Mice, Inbred C57BL; Mice, Transgenic; Models, Biological; NF-kappa B - metabolism; Oncogenes; Original; original-article; Pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Protein Stability; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins p21(ras) - metabolism; ras Proteins - metabolism; Receptor for Advanced Glycation End Products; Receptors, Immunologic - metabolism; Signal Transduction; Transcriptional Activation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.445

A hypoxic tumor microenvironment is characteristic of many cancer types, including one of the most lethal, pancreatic cancer. We recently demonstrated that the receptor for advanced glycation end products (RAGE) has an important role in promoting the development of pancreatic cancer and attenuating the response to chemotherapy. We now demonstrate that binding of RAGE to oncogenic KRAS facilitates hypoxia-inducible factor 1 (HIF1)
α
activation and promotes pancreatic tumor growth under hypoxic conditions. Hypoxia induces NF-
κ
B-dependent and HIF1
α
-independent RAGE expression in pancreatic tumor cells. Moreover, the interaction between RAGE and mutant KRAS increases under hypoxia, which in turn sustains KRAS signaling pathways (RAF-MEK-ERK and PI3K-AKT), facilitating stabilization and transcriptional activity of HIF1
α
. Knock down of RAGE
in vitro
inhibits KRAS signaling, promotes HIF1
α
degradation, and increases hypoxia-induced pancreatic tumor cell death. RAGE-deficient mice have impaired oncogenic KRAS-driven pancreatic tumor growth with significant downregulation of the HIF1
α
signaling pathway. Our results provide a novel mechanistic link between NF-
κ
B, KRAS, and HIF1
α
, three potent molecular pathways in the cellular response to hypoxia during pancreatic tumor development and suggest alternatives for preventive and therapeutic strategies.