NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer.
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.
Ding
Yunfei
Y
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
Tong
Min
M
Liu
Shuqian
S
Moscow
Jeffrey A
JA
Tai
Hsin-Hsiung
HH
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology*; D015232:Dinoprostone / Q000378:metabolism; D015870:Gene Expression; D016147:Genes, Tumor Suppressor / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D006911:Hydroxyprostaglandin Dehydrogenases / Q000187:drug effects / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology*; D051379:Mice; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018960:Hyaluronan Receptors; D012313:RNA; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D006821:Hyaluronoglucosaminidase; D015232:Dinoprostone