15-Hydroxyprostaglandin dehydrogenase as a novel molecular target for cancer chemoprevention and therapy

Biochem Pharmacol. 2011 Nov 15;82(10):1352-60. doi: 10.1016/j.bcp.2011.08.005. Epub 2011 Aug 11.

Abstract

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in arachidonic acid cascade, plays a key role in the biosynthesis of prostaglandin E(2) (PGE(2)) upon inflammatory insults. Overproduction of PGE(2) stimulates proliferation of various cancer cells, confers resistance to apoptosis of cancerous or transformed cells, and accelerates metastasis and angiogenesis. Excess PGE(2) undergoes metabolic inactivation which is catalyzed by NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In this context, 15-PGDH has been speculated as a physiological antagonist of COX-2 and a tumor suppressor. Thus, overexpression of 15-PGDH has been known to protect against experimentally induced carcinogenesis and renders the cancerous or transformed cells susceptible to apoptosis by counteracting oncogenic action of PGE(2). In contrast, silence of 15-PGDH is observed in some cancer cells, which is associated with epigenetic modification, such as DNA methylation and histone deacetylation, in the promoter region of 15-PGDH. A variety of compounds capable of inducing the expression of 15-PGDH have been reported, which include the histone deacetylase inhibitors, nonsteroidal anti-inflammatory drugs, and peroxisome proliferator-activated receptor-gamma agonists. Therefore, 15-PGDH may be considered as a novel molecular target for cancer chemoprevention and therapy. This review highlights the role of 15-PGDH in carcinogenesis and its regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / antagonists & inhibitors*
  • Hydroxyprostaglandin Dehydrogenases / genetics
  • Hydroxyprostaglandin Dehydrogenases / metabolism*
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology*
  • Neoplasms / prevention & control

Substances

  • Antineoplastic Agents
  • Hydroxyprostaglandin Dehydrogenases
  • 15-hydroxyprostaglandin dehydrogenase