Upregulated Apelin Signaling in Pancreatic Cancer Activates Oncogenic Signaling Pathways to Promote Tumor Development - Archive ouverte HAL Access content directly
Journal Articles International Journal of Molecular Sciences Year : 2022

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

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Carline Chaves-Almagro
  • Function : Author
Johanna Auriau
  • Function : Author
Alizée Dortignac
  • Function : Author
Pascal Clerc
  • Function : Author
Hubert Lulka
  • Function : Author
Simon Deleruyelle
  • Function : Author
Fabrice Projetti
  • Function : Author
Jessica Nakhlé
  • Function : Author
Audrey Frances
  • Function : Author
Judit Berta
  • Function : Author
Véronique Gigoux
  • Function : Author
Daniel Fourmy
  • Function : Author
Marlène Dufresne
  • Function : Author
Anne Gomez-Brouchet
  • Function : Author
Julie Guillermet-Guibert
Pierre Cordelier
Bernard Knibiehler
  • Function : Author
Ralf Jockers
  • Function : Author
Philippe Valet
  • Function : Author
Yves Audigier
  • Function : Author
Bernard Masri

Abstract

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.

Dates and versions

hal-03782763 , version 1 (21-09-2022)

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Carline Chaves-Almagro, Johanna Auriau, Alizée Dortignac, Pascal Clerc, Hubert Lulka, et al.. Upregulated Apelin Signaling in Pancreatic Cancer Activates Oncogenic Signaling Pathways to Promote Tumor Development. International Journal of Molecular Sciences, 2022, 23 (18), pp.10600. ⟨10.3390/ijms231810600⟩. ⟨hal-03782763⟩
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