15-Hydroxyprostaglandin dehydrogenase (15-PGDH) and lung cancer

Abstract

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) catalyzes NAD⁺-linked oxidation of 15 (S)-hydroxyl group of prostaglandins and lipoxins and is the key enzyme responsible for the biological inactivation of these eicosanoids. The enzyme was found to be under-expressed as opposed to cyclooxygenase-2 (COX-2) being over-expressed in lung and other tumors. A549 human lung adenocarcinoma cells were used as a model system to study the role of 15-PGDH in lung tumorigenesis. Up-regulation of COX-2 expression by pro-inflammatory cytokines in A549 cells was accompanied by a down-regulation of 15-PGDH expression. Over-expression of COX-2 but not COX-1 by adenoviral-mediated approach also attenuated 15-PGDH expression. Similarly, over-expression of 15-PGDH by the same strategy inhibited IL-1β-induced COX-2 expression. It appears that the expression of COX-2 and 15-PGDH is regulated reciprocally. Adenoviral-mediated transient over-expression of 15-PGDH in A549 cells resulted in apoptosis. Xenograft studies in nude mice also showed tumor suppression with cells transiently over-expressing 15-PGDH. However, cells stably over-expressing 15-PGDH generated tumors faster than those control cells. Examination of different clones of A549 cells stably expressing different levels of 15-PGDH indicated that the levels of 15-PGDH expression correlated positively with those of mesenchymal markers, and negatively with those of epithelial markers. It appears that the stable expression of 15-PGDH induces epithelial-mesenchymal transition (EMT) which may account for the tumor promotion in xenograft studies. A number of anti-cancer agents, such as transforming growth factor-β1 (TGF-β1), glucocorticoids and some histone deacetylase inhibitors were found to induce 15-PGDH expression. These results suggest that tumor suppressive action of these agents may, in part, be related to their ability to induce 15-PGDH expression.

Introduction

Lung cancer is the highest mortality of all cancers among men and women in the U.S. The 5-year survival rate is only 8–14% and has improved marginally in the last 25 years despite extensive research efforts [1]. New approaches for the management of lung cancer are very much needed. One of the most significant approaches so far is to identify risk factors that are associated with the development of lung cancer and to develop effective measures to curtail or to eliminate the impact of these risk factors. One such potential target is the enzyme called cyclooxygenase (COX) catalyzing the synthesis of prostaglandins (PGs) which appear to be involved in cell proliferation, migration, angiogenesis and tumor metastasis [2].

There are three isoforms of COX reported so far. COX-1 is considered constitutive and is expressed in most cell types [3]. COX-2 is regarded inducible and is expressed in response to mitogens, tumor promoters and inflammatory cytokines in some inflammatory cells and cancer cells [3]. COX-3 is an alternate splicing variant of COX-1 and is expressed in some neural cells [4]. It appears that only COX-2 and its ensuing coupling enzyme responsible for the synthesis of PGE₂, microsomal PGE synthase, were reported to over-express in lung tumors [5], [6]. Consequently, compounds that may inhibit the activities of these two enzymes are of particular value in the management of lung cancer. A notable example is the extensive evaluation of non-steroidal anti-inflammatory drugs (NSAIDs) which are known to target on COX-2 as anti-cancer therapeutics [7]. However, the levels of PGs are controlled not only by the synthetic enzymes but also by the degrading enzyme, a fact that has been overlooked in studying prostaglandins and cancer.

The key enzyme involved in degrading PGE₂ is NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). This enzyme catalyzes the oxidation of 15(S)-hydroxyl group of PGs and lipoxins. The products, 15-keto-metabolites, exhibit greatly reduced biological activities rendering this enzyme being a key enzyme responsible for the biological inactivation of these eicosanoids [8]. Its functional role in cardiovascular and pulmonary systems has been extensively studied. However, its potential role in lung cancer and other cancers remains to be defined. Whether this enzyme is altered in expression in lung tumors much as COX-2 is not clear. Whether its expression is related to COX-2 expression in a specific manner remains to be elucidated. If COX-2 is oncogenic in nature, could its antagonistic enzyme, 15-PGDH, be a tumor suppressor? Could some anti-cancer therapeutics exhibit their action, at least in part, by inducing the expression of tumor suppressive 15-PGDH? These questions have recently been explored by a few interesting and revealing reports.