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Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer
Robert L Keith1, York E Miller, Yasushi Hoshikawa
1Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Denver VA Medical Center, Denver, CO 80220, USA.
Abstract:
Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I(2) (PGI(2), prostacyclin) is a PGH(2) metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI(2) has limited its evaluation in animal models of cancer. We hypothesized that pulmonary overexpression of prostacyclin synthase may prevent the development of murine lung tumors. Transgenic mice with selective pulmonary prostacyclin synthase overexpression were exposed to two distinct carcinogenesis protocols: an initiation/promotion model and a simple carcinogen model. The transgenic mice exhibited significantly reduced lung tumor multiplicity (tumor number) in proportion to transgene expression, a dose-response effect. Moreover, the highest expressing mice demonstrated reduced tumor incidence. To investigate the mechanism for protection, we evaluated PG levels and inflammatory responses. At the time of sacrifice following one carcinogenesis model, the transgenics exhibited only an increase in 6-keto-PGF(1alpha), not a decrease in PGE(2). Thus, elevated PGI(2) levels and not decreased PGE(2) levels appear to be necessary for the chemopreventive effects. When exposed to a single dose of butylated hydroxytoluene, transgenic mice exhibited a survival advantage; however, reduction in alveolar inflammatory response was not observed. These studies demonstrate that manipulation of PG metabolism downstream from COX produces even more profound lung cancer reduction than COX inhibition alone and could be the basis for new approaches to understanding the pathogenesis and prevention of lung cancer.
Insights
Pulmonary overexpression of prostacyclin synthase significantly reduced lung tumors in mice. This suggests manipulating prostaglandin (PG) metabolism offers a novel approach to lung cancer prevention.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Cyclooxygenase (COX) inhibition reduces eicosanoids and prevents lung cancer in animal models.
- Prostaglandin I(2) (PGI(2), prostacyclin) possesses anti-inflammatory, antiproliferative, and antimetastatic properties.
- PGI(2)'s instability has hindered its evaluation in cancer models.
Purpose of the Study:
- To investigate if pulmonary overexpression of prostacyclin synthase can prevent murine lung tumors.
- To explore the mechanistic basis of PGI(2)'s potential chemopreventive effects.
Main Methods:
- Generation of transgenic mice with selective pulmonary prostacyclin synthase overexpression.
- Exposure of transgenic mice to two distinct lung carcinogenesis protocols.
- Evaluation of prostaglandin levels and inflammatory responses in treated mice.
Main Results:
- Transgenic mice showed significantly reduced lung tumor multiplicity in a dose-dependent manner.
- Highest expressing mice exhibited reduced tumor incidence.
- Elevated PGI(2) levels (indicated by 6-keto-PGF(1alpha)) correlated with chemoprevention, while PGE(2) levels were not decreased.
Conclusions:
- Pulmonary prostacyclin synthase overexpression demonstrates potent chemopreventive effects against lung cancer in mice.
- Elevated PGI(2) is crucial for this chemopreventive effect, not decreased PGE(2).
- Targeting prostaglandin metabolism downstream of COX offers superior lung cancer reduction compared to COX inhibition alone.