Upregulated Apelin Signaling in Pancreatic Cancer Activates Oncogenic Signaling Pathways to Promote Tumor Development.

Autor: Chaves-Almagro C; Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France., Auriau J; Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France., Dortignac A; Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France., Clerc P; INSERM ERL1226, CNRS UMR 5215, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France., Lulka H; Centre de Recherches en Cancérologie de Toulouse, INSERM, CNRS, Université Paul Sabatier, Université de Toulouse, 31037 Toulouse, France., Deleruyelle S; Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France., Projetti F; Department of Pathology, IUCT-Oncopole, 31100 Toulouse, France., Nakhlé J; Centre de Recherches en Cancérologie de Toulouse, INSERM, CNRS, Université Paul Sabatier, Université de Toulouse, 31037 Toulouse, France., Frances A; Centre de Recherches en Cancérologie de Toulouse, INSERM, CNRS, Université Paul Sabatier, Université de Toulouse, 31037 Toulouse, France., Berta J; Department of Tumor Biology, National Koranyi Institute of Pulmonology, 1121 Budapest, Hungary., Gigoux V; INSERM ERL1226, CNRS UMR 5215, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France., Fourmy D; INSERM ERL1226, CNRS UMR 5215, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France., Dufresne M; Centre de Recherches en Cancérologie de Toulouse, INSERM, CNRS, Université Paul Sabatier, Université de Toulouse, 31037 Toulouse, France., Gomez-Brouchet A; Department of Pathology, IUCT-Oncopole, 31100 Toulouse, France., Guillermet-Guibert J; Centre de Recherches en Cancérologie de Toulouse, INSERM, CNRS, Université Paul Sabatier, Université de Toulouse, 31037 Toulouse, France., Cordelier P; Centre de Recherches en Cancérologie de Toulouse, INSERM, CNRS, Université Paul Sabatier, Université de Toulouse, 31037 Toulouse, France., Knibiehler B; Centre de Recherches en Cancérologie de Toulouse, INSERM, CNRS, Université Paul Sabatier, Université de Toulouse, 31037 Toulouse, France., Jockers R; Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Cité, 75014 Paris, France., Valet P; Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France.; RESTORE, UMR 1301-Inserm 5070-CNRS EFS, Université de Toulouse, 31100 Toulouse, France., Audigier Y; Centre de Recherches en Cancérologie de Toulouse, INSERM, CNRS, Université Paul Sabatier, Université de Toulouse, 31037 Toulouse, France., Masri B; Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, UPS, Toulouse III, 31432 Toulouse, France.; Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Cité, 75014 Paris, France.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2022 Sep 13; Vol. 23 (18). Date of Electronic Publication: 2022 Sep 13.
DOI: 10.3390/ijms231810600
Abstrakt: Despite decades of effort in understanding pancreatic ductal adenocarcinoma (PDAC), there is still a lack of innovative targeted therapies for this devastating disease. Herein, we report the expression of apelin and its receptor, APJ, in human pancreatic adenocarcinoma and its protumoral function. Apelin and APJ protein expression in tumor tissues from patients with PDAC and their spatiotemporal pattern of expression in engineered mouse models of PDAC were investigated by immunohistochemistry. Apelin signaling function in tumor cells was characterized in pancreatic tumor cell lines by Western blot as well as proliferation, migration assays and in murine orthotopic xenograft experiments. In premalignant lesions, apelin was expressed in epithelial lesions whereas APJ was found in isolated cells tightly attached to premalignant lesions. However, in the invasive stage, apelin and APJ were co-expressed by tumor cells. In human tumor cells, apelin induced a long-lasting activation of PI3K/Akt, upregulated β-catenin and the oncogenes c-myc and cyclin D1 and promoted proliferation, migration and glucose uptake. Apelin receptor blockades reduced cancer cell proliferation along with a reduction in pancreatic tumor burden. These findings identify the apelin signaling pathway as a new actor for PDAC development and a novel therapeutic target for this incurable disease.
Databáze: MEDLINE
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