NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer

• Published in: Carcinogenesis (New York) 2005-01, Vol.26 (1), p.65-72
• Main Authors: Ding, Yunfei, Tong, Min, Liu, Shuqian, Moscow, Jeffrey A., Tai, Hsin-Hsiung
• Format: Article
• Language: English
• Subjects: 15-PGDH; Animals; Apoptosis - physiology; Biological and medical sciences; Blotting, Western; Carcinogenesis, carcinogens and anticarcinogens; Carcinoma, Non-Small-Cell Lung - enzymology; COX; cyclooxygenase; Dinoprostone - metabolism; GAPDH; Gene Expression; Genes, Tumor Suppressor - drug effects; Genes, Tumor Suppressor - physiology; glyceraldehyde-3-phosphate dehydrogenase; Humans; Hyaluronan Receptors - biosynthesis; Hyaluronoglucosaminidase - pharmacology; hydroxyprostaglandin dehydrogenase; Hydroxyprostaglandin Dehydrogenases - drug effects; Hydroxyprostaglandin Dehydrogenases - metabolism; interleukin; Lung cancer; Lung Neoplasms - enzymology; m-PGE2; Medical sciences; Mice; microsomal PGE2; non-small cell lung carcinoma; NSCLC; PARP; poly(ADP-ribose) polymerase; prostaglandin; Reverse Transcriptase Polymerase Chain Reaction; reverse transcription–polymerase chain reaction; RNA - analysis; RT–PCR; Tumors
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/bgh277

It has been reported that two inducible prostaglandin synthetic enzymes, cylooxygenase-2 (COX-2) and microsomal PGE synthase, are over-expressed in non-small cell lung cancer (NSCLC). Using quantitative reverse transcription–polymerase chain reaction, we analyzed RNA levels of the key prostaglandin catabolic enzyme, NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH), in 19 pairs of NSCLC tumors and adjacent non-malignant tissue from the same patient. We found that 100% of tumor-tissue pairs showed at least a 2-fold decrease and 61% showed a 10-fold decrease. This suggests that the increased expression of COX-2 and PGE synthase in tumors may work in concert with the decreased expression of 15-PGDH to amplify an increase in tissue levels of proliferative PGE2. To further explore if 15-PGDH is related to tumorigenesis, athymic nude mice were injected with control A549 cells or cells transiently over-expressing wild-type or mutant 15-PGDH (Y151F). It was found that mice injected with control A549 cells or with cells expressing mutant enzyme produced tumors normally. However, mice injected with A549 cells expressing wild-type 15-PGDH had a significant decrease in tumor growth. Examining the effects of 15-PGDH expression on cellular changes in A549 cells, we found that over-expression of 15-PGDH induced apoptosis of A549 cells as evidenced by fragmentation of DNA, activation of pro-caspase 3, cleavage of poly(ADP-ribose) polymerase and decreased expression of Bcl-2. We also found that the expression of 15-PGDH was negatively related to that of pro-adhesive and invasive CD44. Furthermore, the expression of 15-PGDH was found to be stimulated by hyaluronidase. These results suggest that 15-PGDH may decrease the level of proliferative PGE2, induce apoptosis and function like a tumor suppressor.