Carcinogenesis Advance Access first published online on September 9, 2004
This version published online on September 9, 2004
Carcinogenesis, doi:10.1093/carcin/bgh277
© 2004 by Oxford University Press
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1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536
* To whom correspondence should be addressed. E-mail: htail{at}uky.edu.
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 RT-PCR, 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 A-549 cells as evidenced by fragmentation of DNA, activation of pro-caspase 3, cleavage of PARP and decreased expression of Bcl-2. We also found that the expression of 15-PGDH was parallel to that of anti-invasive E-cadherin, but 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. 1 Yunfei Ding and Min Tong contributed equally to this work.
Revised July 6, 2004
Accepted August 27, 2004
CANCER BIOLOGY
NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH) behaves as a tumor suppressor in lung cancer
2 Department of Pediatrics, College of Medicine, University of Kentucky, Lexington, KY 40536
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