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Nucleotide-binding domain of phosphoglycerate kinase 1 reduces tumor growth by suppressing COX-2 expression

Ming-Yi Ho1, Shye-Jye Tang, Wailap V Ng

  • 1Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Department of Education and Research, Taipei City Hospital, Taipei, Taiwan.

Cancer Science
|August 25, 2010
PubMed

Insights

Phosphoglycerate kinase 1 (PGK-1) inhibits tumor growth by targeting COX-2, independent of its catalytic activity. The nucleotide-binding domain (NBD) of PGK-1 is responsible for this COX-2 suppression, likely via mRNA destabilization.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Phosphoglycerate kinase 1 (PGK-1) is a key glycolytic enzyme with known roles in angiogenesis.
  • Previous studies indicated PGK-1 overexpression reduces Lewis lung carcinoma (LLC-1) tumor growth by downregulating COX-2.
  • PGK-1 possesses two domains: a catalytic domain (CD) and a nucleotide-binding domain (NBD).

Purpose of the Study:

  • To determine which functional domain of PGK-1 mediates its antitumor effects.
  • To investigate the role of PGK-1 domains in COX-2 downregulation and tumor invasiveness.

Main Methods:

  • LLC-1 cells were engineered to overexpress full-length PGK-1, CD, or NBD.
  • In vitro cell growth and in vivo tumorigenicity, invasiveness, and tumor growth were evaluated.
  • COX-2 expression, mRNA stability, and prostaglandin E2 levels were assessed.

Main Results:

  • Overexpression of full-length PGK-1, CD, or NBD reduced tumor invasiveness in vivo.
  • Tumor growth retardation was observed with full-length PGK-1, CD, and NBD overexpression.
  • COX-2 suppression, reduced mRNA stability, and lower prostaglandin E2 levels were specifically linked to full-length PGK-1 and NBD overexpression, not CD.

Conclusions:

  • The antitumor effects of PGK-1, specifically COX-2 suppression, are independent of its catalytic activity.
  • The nucleotide-binding domain (NBD) of PGK-1 is crucial for targeting COX-2.
  • PGK-1's NBD likely destabilizes COX-2 mRNA transcripts through its mRNA-binding properties, leading to reduced COX-2 expression and tumor growth inhibition.

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