Nucleotide-binding domain of phosphoglycerate kinase 1 reduces tumor growth by suppressing COX-2 expression.
ABSTRACT 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.
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ABSTRACT: The generation of an "angiogenic switch" is essential for tumor growth, yet its regulation is poorly understood. In this investigation, we explored the linkage between metastasis and angiogenesis through CXCL12/CXCR4 signaling. We found that CXCR4 regulates the expression and secretion of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Overexpression of PGK1 reduced the secretion of vascular endothelial growth factor and interleukin-8 and increased the generation of angiostatin. At metastatic sites, however, high levels of CXCL12 signaling through CXCR4 reduced PGK1 expression, releasing the angiogenic response for metastastic growth. These data suggest that PGK1 is a critical downstream target of the chemokine axis and an important regulator of an "angiogenic switch" that is essential for tumor and metastatic growth.Cancer Research 02/2007; 67(1):149-59. · 8.65 Impact Factor
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ABSTRACT: Preclinical studies suggest that cyclooxygenase (COX)-2 may be involved in the molecular pathogenesis of some types of lung cancer. Most of the available studies point to its involvement in non-small cell lung cancer. Survival of patients with non-small cell lung cancer expressing high levels of COX-2 is markedly reduced. Treatment of humans with the selective COX-2 inhibitor celecoxib augments the antitumor effects of chemotherapy in patients with non-small cell lung cancer. COX-2 has been shown to regulate some aspects of tumor-associated angiogenesis. Most of the results we have published point to effects on the regulation of vascular endothelial growth factor. However, prostaglandins derived from COX-2 affect other signaling pathways as well, such as the epidermal growth factor and its receptor. Others have recently shown that non-small cell lung cancer exhibits a COX-2 downstream enzyme expression pattern that is altered in lung tumor cells and tumor-supplying vessels. Therefore, COX-2 and prostaglandins may have a major impact on lung tumor progression and tumor-associated inflammation. Clinical trials currently underway are exploring the potential of targeting COX-2 in lung cancer.Clinical Cancer Research 07/2004; 10(12 Pt 2):4266s-4269s. · 7.84 Impact Factor
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ABSTRACT: The human X-linked phosphoglycerate kinase (PGK) gene, which is expressed in all somatic cells, was cloned and its structure was determined. The gene is interrupted by 10 introns and spans 23 kilobases. When projected on the three-dimensional structure of the PGK protein molecule, splice junctions are located between established peptide domains. In particular, an intron separates the two mononucleotide subdomains of the ATP-binding region, and additional introns divide each of these subdomains between their characteristic beta-strands. Similar correlations are found in the bipartite NAD-binding domains of alcohol dehydrogenase and glyceraldehyde-3-phosphate dehydrogenase. Furthermore, in each case the nucleotide-binding domain is separated from the catalytic domain by at least one intron. The homology of the exon organization in structurally similar regions of these three enzymes suggests that a nucleotide-binding domain evolved by gene duplication and was subsequently dispersed to different proteins through a process of intron-mediated recombination.Proceedings of the National Academy of Sciences 11/1985; 82(20):6965-9. · 9.74 Impact Factor