TY - JOUR

T1 - The P2X7 Receptor Stimulates IL-6 Release from Pancreatic Stellate Cells and Tocilizumab Prevents Activation of STAT3 in Pancreatic Cancer Cells

AU - Magni, Lara

AU - Bouazzi, Rayhana

AU - Heredero Olmedilla, Hugo

AU - Petersen, Patricia S. S.

AU - Tozzi, Marco

AU - Novak, Ivana

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - pancreatic cancer

KW - PDAC

KW - pancreatic stellate cells

KW - IL-6

KW - Tocilizumab

KW - STAT3

KW - fibrosis

KW - eATP

KW - UP-REGULATION

KW - ATP RELEASE

KW - MOUSE

KW - FIBROBLASTS

KW - CONTRIBUTES

KW - ANTAGONISTS

KW - METABOLISM

KW - PRESSURE

KW - ROLES

KW - BASAL

U2 - 10.3390/cells10081928

DO - 10.3390/cells10081928

M3 - Journal article

C2 - 34440697

VL - 10

JO - Cells

JF - Cells

SN - 2073-4409

IS - 8

M1 - 1928

ER -