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-beta1 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-gamma) 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.
Tang
Shye-Jye
SJ
Institute of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung, Taiwan, ROC.
Ho
Ming-Yi
MY
Cho
Huan-Chieh
HC
Lin
Ying-Chun
YC
Sun
Guang-Huan
GH
Chi
Kwan-Hwa
KH
Wang
Yu-Shan
YS
Jhou
Ren-Shiang
RS
Yang
Winnie
W
Sun
Kuang-Hui
KH
D000818:Animals; D015153:Blotting, Western; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D042783:Endothelial Cells; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D010735:Phosphoglycerate Kinase / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation
D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C528165:Pgk1 protein, mouse; D010735:Phosphoglycerate Kinase; D015232:Dinoprostone