We found that the p-Stat3 protein level was significantly decreased in SW1990 cells after treatment with AG490 and markedly increased in Capan-2 cells after treatment with IL-6. These results demonstrate that AG490 strongly suppresses Stat3 activity and that IL-6 promotes Stat3 activity in pancreatic cancer cell lines. Stat3 is an oncogene that is constitutively active in many tumor types and promotes cell proliferation and survival[21, 25]. Inappropriate see more and constitutive activation of Stat3 may be responsible for pancreatic
cancer progression by regulating the expression of target genes, such as c-Myc, Bcl-xL, https://www.selleckchem.com/products/azd5363.html p21WAF1, and cyclinD1, and functional inactivation of Stat3 by dominant-negative Stat3 or AG490 could inhibit the proliferation and promote the apoptosis of pancreatic cancer cells[8, 26]. Moreover, evidence indicates that constitutive activation of Stat3 influences invasion and metastasis. For example, activation of Stat3 in thymic epithelial tumors, colorectal adenocarcinoma, and Bafilomycin A1 nmr cutaneous squamous cell carcinoma correlates with invasion and lymph node metastasis. In our study, we examined the effects of AG490 and IL-6 on growth capability of pancreatic cancer cells. The MTT assay indicated that IL-6 can stimulate the growth of Capan-2
cells, and proliferation of SW1990 cells was attenuated when cells were treated with AG490. We examined the invasive ability of these cells using a cell invasion assay kit. We found that SW1990 cells showed a weaker level of invasion after treatment with AG490. In contrast, Capan-2 cell invasion was significantly increased by IL-6. Therefore, there is a strong relationship between Stat3 activity
Sitaxentan and the invasive ability of human pancreatic cancer cells. Tumor invasion and metastasis depend on angiogenesis, which is the formation of new blood vessels from a pre-existing network of capillaries. VEGF is known to be a potent angiogenic mitogen that plays an important role in tumor angiogenesis, invasion, and metastasis. The role of Stat3 in angiogenesis was first shown when VEGF was found to be a direct target of Stat3 in mouse melanoma cells and then confirmed by a study in a human pancreatic cancer system. A recent study has reported that constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. Furthermor, a Stat3-responsive element on the VEGF promoter was identified using a protein-DNA binding assay and confirmed using a promoter mutagenesis assay. Our previous study also found that silencing of the Stat3 gene by RNAi decreases VEGF expression in the pancreatic cancer cell line SW1990[ 23 ]. In the present study, we also found that AG490 significantly decreased the mRNA and protein expression of VEGF in SW1990 cells, and IL-6 markedly increased the VEGF mRNA and protein expression in Capan-2 cells.