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

Abstract

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.

Repurposing the Antibacterial Agents Peptide 19-4LF and Peptide 19-2.5 for Treatment of Cutaneous Leishmaniasis

“…Our findings showed an activation of Th1-associated genes (IL-12, TNFa and iNOS) when the gene expression level of the P2X7 receptor was reduced in skin lesions of L. major infected mice. In addition, a significant increase in IL-6 gene expression levels was observed in the spleen in accordance with studies revealing that the P2X7 receptor promoted the secretion of the inflammatory cytokine IL-6 [59,60]. Our findings supported the P2X7 receptor as a therapeutic target for cutaneous leishmaniasis.…”

Current Trends and Research Hotspots in Pancreatic Stellate Cells: A Bibliometric Study

“…Particularly, PSCs promote the proliferation, invasion, angiogenesis, immune-escape, and chemo-resistance of pancreatic ductal adenocarcinoma. Activated PSCs secret elevated levels of cytokines and growth factors, such as IL-6 ( 43 ) and vascular endothelial growth factor ( 44 ). These secreted factors promote the proliferation, invasion, and angiogenesis of cancer cells ( 45 ).…”

STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer

“…In a mouse transplantation tumor model, tocilizumab blockade of IL-6 significantly abrogated mesenchymal stromal cell-mediated tumor promotion and delayed tumor formation [ 97 ], and inhibition of IL-6 signaling by tocilizumab partially reversed the EMT phenotype of pancreatic ductal epithelial Kras mutant cells [ 98 ]. PSCs and cancer cells in pancreatic cancer TME release ATP, which activates the P2X7 receptor, promoting PSC proliferation, collagen secretion, and IL-6 secretion, and P2X7R-conditioned cultures also stimulate PSCs to activate the JAK/STAT3 signaling pathway in cancer cells, leading to pancreatic cancer cell migration, which is inhibited by tocilizumab [ 99 ].…”