Carcinogenesis Advance Access published online on April 22, 2006
Carcinogenesis, doi:10.1093/carcin/bgl053
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1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082
* To whom correspondence should be addressed. Human lung adenocarcinoma cells, A549, possess the capacity of expressing both cyclooxygenase-2 (COX-2) and NAD+-linked 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Resting cells express little COX-2, but significant level of 15-PGDH. IL-1
Received November 15, 2005
Revised March 21, 2006
Accepted April 13, 2006
CANCER BIOLOGY
Reciprocal regulation of cyclooxygenase-2 and 15-hydroxyprostaglandin dehydrogenase expression in A549 human lung adenocarcinoma cells
Min Tong 1 1,
Yunfei Ding 1 1,
and
Hsin-Hsiung Tai 1 *
Hsin-Hsiung Tai, E-mail: htai1{at}uky.edu
Abstract 
, TNF-
or phorbol ester (PMA) induced the expression of COX-2 as revealed by Western blot analysis. Combination of PMA and IL-1 or TNF- induced synergistically the expression of COX-2. Interestingly, cytokines and cytokine plus PMA-induced expression of COX-2 were accompanied by a down-regulation of 15-PGDH. This was evident from both the Western blot analysis and activity assay of 15-PGDH. It appears that the higher the expression of COX-2 was induced, the lower the expression of 15-PGDH was found. This was further supported by the observation that over-expression of COX-2 but not COX-1 by adenovirus-mediated approach led to a decrease in 15-PGDH expression indicating the specificity of COX-2. Furthermore, down-regulation of the IL-1-induced expression of COX-2 by siRNA approach resulted in an increase in the expression of 15-PGDH by COX-2-siRNA but not by COX-1-siRNA indicating that it was indeed the expression of COX-2 attenuating the expression of 15-PGDH. The IL-1-induced reduction of the expression of 15-PGDH was shown not to be mediated by COX-2-derived products since the presence of COX-2 inhibitors did not block the attenuation of the expression of 15-PGDH. Exogenous PGE2 also did not induce the reduction of the expression of 15-PGDH. However, over-expression of 15-PGDH by transfection with recombinant plasmid encoding 15-PGDH or adenovirus-mediated approach attenuated IL-1-induced expression of COX-2. On the contrary, down-regulation of 15-PGDH expression by 15-PGDH-siRNA or 15-PGDH-antisense approach resulted in an increase in IL-1-induced expression of COX-2 but not that of COX-1. In fact, it was further observed that A549 clones expressing different degrees of 15-PGDH showed also different levels of COX-2 expression after IL-1 induction. The levels of IL-1-induced COX-2 expression appeared to correlate inversely with those of 15-PGDH expression in the cells. These results support the contention that COX-2 and 15-PGDH are regulated reciprocally in A549 cells.
1. The first two authors contributed equally to this work.
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