Interleukin-1 receptor antagonist inhibits angiogenesis via blockage IL-1 alpha/PI3K/NF-kappa B pathway in human colon cancer cell

Purpose: This article investigates the relationship between cancer cells and stromal cells in carcinoma cell living microenvironment and elucidates the mechanism that interleukin-1 receptor antagonist (IL-1RA) blocks metastatic potential in colon cancer. Methods: Western blot and RT-PCR assay were used to determine the expression of hepatocyte growth factor (HGF) and IL-1a in colon carcinoma cells and stromal cells. Effect of IL-1RA and HGF on metastatic potential of colon cancer cells were examined by proliferation, invasion, and angiogenesis assays. The interactional role of IL-1RA and HGF were detected by ELISA assay, invasion, and angiogenesis assay making up a co-culture system consisting of stromal and colon cancer cells in cells living microenvironment. Results: IL-1a was expressed in human umbilical vein endothelial cells (HUVECs) and HT-29 and WiDr (colon cancer cell lines with higher liver metastatic potential). HGF was expressed only in fibroblast. HGF secretion from fibroblasts was significantly inhibited by IL-1RA (P<0.01). Furthermore, IL-1RA could significantly inhibit migration, proliferation, and angiogenesis of HUVECs (P<0.01). In the double co-culture system, there is a high liver metastatic potential of colon cancer cell line (HT-29) because it can secrete autocrine IL-1a, significantly enhanced angiogenesis compared with low liver metastatic cell line (CaCo-2) (P<0.01), which does not secrete IL-1a. On the contrary, blockage of autocrine IL-1a by IL-1RA might significantly decrease metastatic potential of colon carcinoma cells through downregulation of IL-1 alpha/PI3K/NF-kappa B pathway. Conclusion: IL-1 receptor antagonist (IL-1RA) is an important inhibitor in metastatic process of colon carcinoma cell. Based on the above results, we suggest that IL-1RA may be a promising new therapeutic approach in inhibiting colon cancer with IL-1-producing patients.