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.

• Authors: Ming-Yi Ho, Shye-Jye Tang, Wailap V Ng, Winnie Yang, Shr-Jeng J Leu, Ying-Chun Lin, Chi-Kuang Feng, Jung-Sung Sung, Kuang-Hui Sun
• Journal: Cancer science (Cancer Sci) Vol. 101 Issue 11 Pg. 2411-6 (Nov 2010) ISSN: 1349-7006 [Electronic] England
• PMID: 20731664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2010 Japanese Cancer Association.

Chemical References

• Nucleotides
• Transforming Growth Factor beta1
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Pgk1 protein, mouse
• Phosphoglycerate Kinase
• Dinoprostone

Topics

• Animals
• Binding Sites (genetics)
• Blotting, Western
• Carcinoma, Lewis Lung (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cyclooxygenase 2 (genetics, metabolism)
• Dinoprostone (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Gene Expression Regulation, Neoplastic
• Lung Neoplasms (genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Nucleotides (metabolism)
• Phosphoglycerate Kinase (genetics, metabolism)
• RNA Stability
• Reverse Transcriptase Polymerase Chain Reaction
• Transfection
• Transforming Growth Factor beta1 (metabolism)
• Tumor Burden