Neutrophil-Secreted Proteinase 3 Mediates Metastasis of Prostate Cancer Cells Expressing RAGE to the Bone Marrow

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Human prostate cancer non-randomly metastasizes to the bone marrow, but the biological basis for such site-specific tropism remains largely unresolved. Differential expression of molecules in the bone marrow microenvironment "niche" has recently been proposed to play a role. In previous work, combinatorial selection of random peptide libraries in end-of-life cancer patients has revealed an unexpected interaction between the receptor for advanced glycation end products (RAGE), a molecule expressed on malignant cell surfaces in advanced prostate cancer, and proteinase 3 (PR3), a serine protease abundantly present on neutrophils and promyelocytes within the bone marrow microenvironment. Because RAGE is selectively overexpressed in prostate cancer bone metastases, we hypothesize here that its specific binding to PR3 might mediate homing of prostate cancer cells to the bone marrow. We demonstrate that PR3 non-proteolytically binds to RAGE on prostate cancer cell surfaces and thereby promotes tumor cell activation and motility. We also show that the downstream signal transduction cascade triggered by RAGE/PR3 binding involves p44/42 (Erk1/2) and JNK1 phosphorylation. Finally, we use a mouse model of experimental metastasis to demonstrate that RAGE protein expression on human prostate cancer cells promotes their homing to bone marrow within a short time frame. These results validate a functional protein interaction between RAGE and PR3 and uncover a mechanism through which neutrophils mediate prostate cancer cell metastasis to the skeleton. DisclosuresSergeeva:Astellas: Patents & Royalties. Molldrem:Astellas Pharma: Patents & Royalties.