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IL-33 Inhibits Proliferation and Induces of Apoptosis of Pancreatic Cancer Cells
Michael Nicholl*1,2, Yujiang Fang1,2, Elizabeth J. Herrick1, Kathryn M. Cook1
1Surgery, University of Missouri, Columbia, MO; 2Surgical Oncology, Ellis Fischel Cancer Center, Columbia, MO
Background: IL-33, a member of the IL-1 cytokine family, acts in both an autocrine and paracrine manner by binding its receptor, ST2. The role of IL-33 in host immune responses to infectious pathogens and allergens has been extensively studied, whereas very little data exists regarding the role of IL-33 in anti-tumor immune responses. No study has been performed to address the direct effect of IL-33 on tumor cell proliferation or apoptosis.
Methods: In the present study, clonogenic survival assay, immunohistochemistry (IHC), TUNEL staining, proliferation and caspase-3 activity kits were used to evaluate the effects of IL-33 on cell survival, proliferation and apoptosis of a pancreatic cancer cell line, MiaPaCa-2. We further investigated the possible molecular mechanisms by using RT-PCR, IHC, and Western blot.
Results: We found that the percentage of colonies of MiaPaCa-2 cells, PCNA+ cells and the OD value of cancer cells were all decreased after incubation with IL-33. TUNEL+ cells and the relative caspase-3 activity in cancer cells were increased in the presence of IL-33. The anti-proliferative effect of IL-33 on cancer cells correlated with downregulation of pro-proliferative molecule cdk2 and cdk4 and upregulation of anti-proliferative molecule p15, p21 and p53. The pro-apoptotic effect of IL-33 correlated with downregulation of anti-apoptotic molecule FLIP and upregulation of pro-apoptotic molecule TRAIL.
Conclusions: IL-33 inhibits proliferation and induces of apoptosis of pancreatic cancer cells in vivo. Manipulation of the IL-33/ST2 pathway might be a promising strategy to treat pancreatic cancer.
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