gardiquimod and Pancreatic-Neoplasms

Toll-like receptors (TLRs) are critical in the induction of the immune response in tumor development. TLR7 has previously been demonstrated to be associated with the development of pancreatic cancer, and the release of cytokines and chemokines from other types of cancer cell; however, the specific expression induced by TLR7 agonists in pancreatic cancer cells remains to be elucidated. The present study aimed to investigate the effects of the TLR7 agonist, gardiquimod, on ERK1/2 signaling pathway, and on the expression of genes involved in the pathogenesis of cancer, including phosphatase and tensin homolog deleted on chromosome 10 (PTEN), p53, type Ⅲ interferon (IFN-λ1), vascular endothelial growth factor (VEGF), matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1). The results demonstrated that activation of TLR7 upregulated the expression levels of certain genes to varying degrees; the expression levels of IFN-λ1 and MMP-9 were increased by ~3 fold, whereas other genes (p53, PTEN, TIMP-1) were upregulated by ~2 fold, and VEGF was marginally upregulated after 10 min. Furthermore, gardiquimod increased the expression levels of phosphorylated-extracellular signal-regulated kinase (ERK)1/2. In addition, PD98059, a specific inhibitor of ERK phosphorylation, inhibited the ability of gardiquimod to activate ERK1/2; consequently weakening the effect of gardiquimod on gene regulation. These findings indicated that the effect of TLR7 agonists, including gardiquimod, on gene expression in BxPC-3 pancreatic cancer cells was partly associated with the mitogen-activated protein kinase-ERK1/2 signaling pathway.

Topics: Aminoquinolines; Cell Line, Tumor; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Interferons; Interleukins; Matrix Metalloproteinase 9; Pancreatic Neoplasms; Phosphorylation; PTEN Phosphohydrolase; Tissue Inhibitor of Metalloproteinase-1; Toll-Like Receptor 7; Tumor Suppressor Protein p53; Up-Regulation; Vascular Endothelial Growth Factor A

Pancreatic cancer is one of the most malignant types of tumor and has a poor prognosis. Toll‑like receptor 7 (TLR7) has been found to be present and have different roles in different types of cancer cells. In the present study, the roles of TLR7 in BxPC‑3 cells, a human pancreatic adenocarcinoma cell line, were investigated. The cells were treated with gardiquimod, an agonist of TLR7, following which the properties of the cells, including proliferation, migration, cell cycle and apoptosis, were analyzed. It was revealed that activation of TLR7 by gardiquimod inhibited cell proliferation and migration, and induced apoptosis of the cells. In addition, gardiquimod downregulated the expression levels of cyclin B1, cyclin E and B‑cell lymphoma 2, while upregulating the expression of B‑cell‑associated X protein. These results suggested that the activation of TLR7 suppresses the progression of pancreatic cancer.

Topics: Aminoquinolines; Apoptosis; B-Lymphocytes; bcl-2-Associated X Protein; beta Catenin; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin E; Dose-Response Relationship, Drug; Down-Regulation; Humans; Imidazoles; Oncogene Proteins; Pancreatic Neoplasms; Toll-Like Receptor 7; Up-Regulation