NAD+-Dependent 15-Hydroxyprostaglandin Dehydrogenase Regulates Levels of Bioactive Lipids in Non–Small Cell Lung Cancer

Abstract

Elevated levels of procarcinogenic prostaglandins (PG) are found in a variety of human malignancies including non-small cell lung cancer (NSCLC). Overexpression of cyclooxygenase-2 and microsomal prostaglandin synthase 1 occurs in tumors and contributes to increased PG 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 and microsomal prostaglandin synthase 1 were commonly increased whereas the amount of 15-PGDH was frequently decreased in NSCLC compared with adjacent normal lung. Reduced expression of 15-PGDH occurred in tumor cells and was paralleled by decreased 15-PGDH activity in tumors. Amounts of PGE 1 , PGE 2 , and PGF 2α , known substrates of 15-PGDH, were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE 2 , a catabolic product of PGE 2 , 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 PGE 1 , PGE 2 , and PGF 2α were markedly increased whereas levels of 13,14-dihydro-15-keto-PGE 2 were decreased in the lungs of 15-PGDH knockout mice compared with wild-type mice or when 15-PGDH was silenced in A549 lung cancer cells. Collectively, these data indicate that 15-PGDH is commonly downregulated in NSCLC, an effect that contributes to the accumulation of multiple bioactive lipids in NSCLC.

Prostaglandin catabolic enzymes as tumor suppressors

“…We found that 100% of human lung tumor-tissue pairs showed a twofold decrease and that 61% showed a tenfold decrease in mRNA levels using quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis [8]. Similar observation of the down-regulation of 15-PGDH in lung tumors was made in other laboratories [9,10]. Similarly, Yan et al [11] showed that median 15-PGDH expression of human colon cancer samples was at an undetectable level and was at least 17-fold below the median expression in normal colons using an assay on GeneChip expression microarrays.…”

Loss of 15-Hydroxyprostaglandin Dehydrogenase Expression Contributes to Bladder Cancer Progression

“…In fact, previous work has suggested that the inhibition of tumor growth by PGDH expressing cells was due more to a regional effect of PGE2 reduction, such as reduced angiogenesis, and less on the direct effects on tumor cells. 11 Tumor PGDH expression clearly affects the tumor milieu, as shown by reduction of PGE2 levels in lung cancers 10 and alteration of antitumoral immune responses. 30 In our study, we show that PGDH knockdown in 9027 shRNA lentivirus-infected RT4 cells permitted PGE2 signaling as measured by cAMP generation, whereas signaling was suppressed in the PGDH-expressing parental lines ( Figure 3E).…”

“…9 PGDH expression has been shown to regulate PGE2 levels in lung cancer. 10 PGDH expression is reduced in colon, breast, gastric and lung cancers, and restoration can inhibit tumorigenesis in xenografts, thus PGDH is recognized as a tumor suppressor in those cancers. [11][12][13][14][15] Therefore, PGDH is important for regulating cancer development and progression.…”

Characterization of an arachidonic acid-deficient (Fads1 knockout) mouse model

“…Collision-induced dissociation of the eicosanoids was performed using argon gas at a cell pressure of 1.6 × 10 Ϫ 3 Torr. Eicosanoids were detected and quantifi ed by multiple reaction mode monitoring of the transitions m/z 351 → 271 for AA-derived PGE 2 and m/z 353 → 317 for DGLA-derived PGE 1 ( 21 ).…”