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Cancer Metabostemness and Metabolic Reprogramming via P2X7 Receptor
Article

The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, 2100 Copenhagen, Denmark
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Author to whom correspondence should be addressed.
Academic Editors: Renata Ciccarelli and Friedrich Haag
Cells 2021, 10(8), 1928; https://doi.org/10.3390/cells10081928
Received: 29 April 2021 / Revised: 30 June 2021 / Accepted: 23 July 2021 / Published: 29 July 2021
(This article belongs to the Special Issue Purine Signaling and Metabolism in Tumors)
Pancreatic stellate cells (PSCs) are important pancreatic fibrogenic cells that interact with pancreatic cancer cells to promote the progression of pancreatic ductal adenocarcinoma (PDAC). In the tumor microenvironment (TME), several factors such as cytokines and nucleotides contribute to this interplay. Our aim was to investigate whether there is an interaction between IL-6 and nucleotide signaling, in particular, that mediated by the ATP-sensing P2X7 receptor (P2X7R). Using human cell lines of PSCs and cancer cells, as well as primary PSCs from mice, we show that ATP is released from both PSCs and cancer cells in response to mechanical and metabolic cues that may occur in the TME, and thus activate the P2X7R. Functional studies using P2X7R agonists and inhibitors show that the receptor is involved in PSC proliferation, collagen secretion and IL-6 secretion and it promotes cancer cell migration in a human PSC-cancer cell co-culture. Moreover, conditioned media from P2X7R-stimulated PSCs activated the JAK/STAT3 signaling pathway in cancer cells. The monoclonal antibody inhibiting the IL-6 receptor, Tocilizumab, inhibited this signaling. In conclusion, we show an important mechanism between PSC-cancer cell interaction involving ATP and IL-6, activating P2X7 and IL-6 receptors, respectively, both potential therapeutic targets in PDAC. View Full-Text
Keywords: pancreatic cancer; PDAC; pancreatic stellate cells; IL-6; Tocilizumab; P2X7R; STAT3; fibrosis; eATP pancreatic cancer; PDAC; pancreatic stellate cells; IL-6; Tocilizumab; P2X7R; STAT3; fibrosis; eATP
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MDPI and ACS Style

Magni, L.; Bouazzi, R.; Heredero Olmedilla, H.; Petersen, P.S.S.; Tozzi, M.; Novak, I. The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells. Cells 2021, 10, 1928. https://doi.org/10.3390/cells10081928

AMA Style

Magni L, Bouazzi R, Heredero Olmedilla H, Petersen PSS, Tozzi M, Novak I. The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells. Cells. 2021; 10(8):1928. https://doi.org/10.3390/cells10081928

Chicago/Turabian Style

Magni, Lara, Rayhana Bouazzi, Hugo Heredero Olmedilla, Patricia S.S. Petersen, Marco Tozzi, and Ivana Novak. 2021. "The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells" Cells 10, no. 8: 1928. https://doi.org/10.3390/cells10081928

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