Phosphoglycerate kinase 1‐overexpressing lung cancer cells reduce cyclooxygenase 2 expression and promote anti‐tumor immunity in vivo

In addition to the known function in the glycolytic pathway, phosphoglycerate kinase 1 (PGK‐1) promotes reduction of plasmin disulfide bonds leading to angiostatin formation and inhibition of tumor angiogenesis. In this study, the effects of PGK‐1 on anti‐ tumor immunity against lung cancer were evaluated using the Tet‐Off control of PGK‐1 expression in the Lewis lung carcinoma (LLC‐1). There was no significant difference in cell proliferation between parental LLC‐1 and LLC‐1 transduced with PGK‐1 (PGK‐LLC‐1). However, expression of PGK‐1 was found to limit tumor growth in mice subcutaneously injected with the cell lines and tumor growth was restored after doxycycline treatment. In addition, the cell invasion ability of PGK‐LLC‐1 became weaker than that of LLC‐1. Expressions of COX‐2, TGF‐β1 and PGE2 were all found to be down‐regulated in PGK‐LLC‐1. PGK‐LLC‐1 cells treated with doxycycline recovered their COX‐2 protein expression. In the presence of conditioned medium from PGK‐LLC‐1, the endothelial cell migration was reduced. Moreover, PGK‐LLC‐1 also stimulated T lymphocytes to express higher levels of Th1 cytokine (IFN‐γ) and lower levels of IL‐10 in comparison with parental LLC‐1. PGK‐LLC‐1 cells restored the growth rate in immunodeficient mice when compared with the growth rate in normal mice. In the tissue sections, reduced COX‐2 expressions and marked infiltrated CD3 T lymphocytes were observed in the PGK‐LLC‐1 injected group. These findings indicate that overexpression of PGK‐1 in LLC‐1 reduces the COX‐2 expression, and, in turn, affect PGE2, cell invasion, angiogenesis, and the immune functions, and finally inhibit the tumor progression. © 2008 Wiley‐Liss, Inc.