Open AccessNucleotide‐binding domain of phosphoglycerate kinase 1 reduces tumor growth by suppressing COX‐2 expression
Author(s) -
Ho MingYi,
Tang ShyeJye,
Ng Wailap V.,
Yang Winnie,
Leu ShrJeng J.,
Lin YingChun,
Feng ChiKuang,
Sung JungSung,
Sun KuangHui
Publication year - 2010
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2010.01691.x
Subject(s) - phosphoglycerate kinase , lewis lung carcinoma , glycolysis , biology , microbiology and biotechnology , in vivo , downregulation and upregulation , kinase , cell culture , biochemistry , metabolism , cancer , enzyme , gene , genetics , metastasis
Phosphoglycerate kinase 1 (PGK‐1) is a multifunctional protein that is involved in the glycolytic pathway and the generation of the angiogenesis inhibitor angiostatin. In a previous study, we showed that the overexpression of full‐length PGK‐1 in Lewis lung carcinoma (LLC‐1) can reduce tumor growth in vivo by downregulation of COX‐2 expression. Phosphoglycerate kinase 1 has two functional domains: a catalytic domain (CD); and a nucleotide‐binding domain (NBD). To identify the functional domain of PGK‐1 responsible for its antitumor effects, we evaluated the tumorigenicity of LLC‐1 cells overexpressing full‐length PGK‐1 (LLC‐1/PGK), CD (LLC‐1/CD), and NBD (LLC‐1/NBD). Although no difference in tumor cell growth was observed in vitro , the tumor invasiveness was reduced in the LLC‐1/PGK, LLC‐1/CD, and LLC‐1/NBD cells compared to parental LLC‐1 cells in vivo . In addition, in vivo tumor growth retardation by LLC‐1/CD and LLC‐1/NBD cells was observed, similar to that by LLC‐1/PGK cells. However, the reduced stability of COX‐2 mRNA and downregulation of the COX‐2 protein and its metabolite, prostaglandin E2, was only found in LLC‐1/PGK and LLC‐1/NBD cells. Low levels of COX‐2 were also observed in the tumor mass formed by the modified cells when injected into mice. The results indicate that COX‐2 suppression by PGK‐1 is independent of its catalytic activity. COX‐2 targeting by PGK‐1 can be attributed to its NBD and is probably a result of the destabilization of COX‐2 gene transcripts brought about by the mRNA‐binding property of PGK‐1. ( Cancer Sci 2010; 101: 2411–2416)