NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase regulates levels of bioactive lipids in non-small cell lung cancer

Elevatedlevels of procarcinogenic prostaglandins (PG) are foundin a variety of human malignancies including non-small cell lung cancer (NSCLC). Overexpression of cyclooxygenase- 2 andmicrosomal prostaglandin synthase 1 occurs in tumors andcontributes to increasedP G synthesis. NAD ⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15- PGDH), the key enzyme responsible for metabolic inactivation of PGs, is down-regulated in various malignancies. The main objective of this study was to elucidate the effect of loss of 15-PGDH on levels of bioactive lipids in NSCLC. We found that levels of cyclooxygenase- 2 andmicrosom al prostaglandin synthase 1 were commonly increased whereas the amount of 15-PGDH was frequently decreased in NSCLC compared with adjacent normal lung. Reducedexpression of 15-PGDH occurredin tumor cells andwas paralleled by decreased 15-PGDH activity in tumors. Amounts of PGE₁, PGE₂, and PGF _2α, known substrates of 15-PGDH, were markedly increased whereas levels of 13,14-dihydro-15- keto-PGE₂, a catabolic product of PGE₂, were markedly reduced in NSCLC compared with normal lung. Complementary in vitro and in vivo experiments were done to determine whether these changes in PG levels were a consequence of down-regulation of 15-PGDH in NSCLC. Similar to NSCLC, amounts of PGE₁, PGE₂, and PGF_2α were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE₂ were decreased in the lungs of 15-PGDH knockout mice comparedwith wild-type mice or when 15-PGDH was silenced in A549 lung cancer cells. Collectively, these data indicate that 15-PGDH is commonly downregulatedin NSCLC, an effect that contributes to the accumulation of multiple bioactive lipids in NSCLC.