Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer

Robert L. Keith, York E. Miller, Yasushi Hoshikawa, Mark D. Moore, Tracy L. Gesell, Bifeng Gao, Alvin M. Malkinson, Heiko A. Golpon, Raphael A. Nemenoff, Mark W. Geraci

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I2 (PGI2, prostacyclin) is a PGH2 metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI2 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, not a decrease in PGE2. Thus, elevated PGI2 levels and not decreased PGE2 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.

Original languageEnglish
Pages (from-to)734-740
Number of pages7
JournalCancer Research
Volume62
Issue number3
Publication statusPublished - 01-02-2002

Fingerprint

Epoprostenol
Lung Neoplasms
Prostaglandin-Endoperoxide Synthases
Lung
Transgenic Mice
Neoplasms
Dinoprostone
Prostaglandins
Carcinogenesis
Animal Models
Prostaglandin H2
Butylated Hydroxytoluene
Eicosanoids
Transgenes
Carcinogens
Anti-Inflammatory Agents
prostacyclin synthetase
Incidence

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Keith, R. L., Miller, Y. E., Hoshikawa, Y., Moore, M. D., Gesell, T. L., Gao, B., ... Geraci, M. W. (2002). Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Research, 62(3), 734-740.
Keith, Robert L. ; Miller, York E. ; Hoshikawa, Yasushi ; Moore, Mark D. ; Gesell, Tracy L. ; Gao, Bifeng ; Malkinson, Alvin M. ; Golpon, Heiko A. ; Nemenoff, Raphael A. ; Geraci, Mark W. / Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. In: Cancer Research. 2002 ; Vol. 62, No. 3. pp. 734-740.
@article{471cfb2880ed4dbfb7e64954dd9704dc,
title = "Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer",
abstract = "Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I2 (PGI2, prostacyclin) is a PGH2 metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI2 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-PGF1α, not a decrease in PGE2. Thus, elevated PGI2 levels and not decreased PGE2 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.",
author = "Keith, {Robert L.} and Miller, {York E.} and Yasushi Hoshikawa and Moore, {Mark D.} and Gesell, {Tracy L.} and Bifeng Gao and Malkinson, {Alvin M.} and Golpon, {Heiko A.} and Nemenoff, {Raphael A.} and Geraci, {Mark W.}",
year = "2002",
month = "2",
day = "1",
language = "English",
volume = "62",
pages = "734--740",
journal = "Cancer Research",
issn = "0008-5472",
number = "3",

}

Keith, RL, Miller, YE, Hoshikawa, Y, Moore, MD, Gesell, TL, Gao, B, Malkinson, AM, Golpon, HA, Nemenoff, RA & Geraci, MW 2002, 'Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer', Cancer Research, vol. 62, no. 3, pp. 734-740.

Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. / Keith, Robert L.; Miller, York E.; Hoshikawa, Yasushi; Moore, Mark D.; Gesell, Tracy L.; Gao, Bifeng; Malkinson, Alvin M.; Golpon, Heiko A.; Nemenoff, Raphael A.; Geraci, Mark W.

In: Cancer Research, Vol. 62, No. 3, 01.02.2002, p. 734-740.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer

AU - Keith, Robert L.

AU - Miller, York E.

AU - Hoshikawa, Yasushi

AU - Moore, Mark D.

AU - Gesell, Tracy L.

AU - Gao, Bifeng

AU - Malkinson, Alvin M.

AU - Golpon, Heiko A.

AU - Nemenoff, Raphael A.

AU - Geraci, Mark W.

PY - 2002/2/1

Y1 - 2002/2/1

N2 - Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I2 (PGI2, prostacyclin) is a PGH2 metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI2 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-PGF1α, not a decrease in PGE2. Thus, elevated PGI2 levels and not decreased PGE2 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.

AB - Inhibition of cyclooxygenase (COX) activity decreases eicosanoid production and prevents lung cancer in animal models. Prostaglandin (PG) I2 (PGI2, prostacyclin) is a PGH2 metabolite with anti-inflammatory, antiproliferative, and antimetastatic properties. The instability of PGI2 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-PGF1α, not a decrease in PGE2. Thus, elevated PGI2 levels and not decreased PGE2 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.

UR - http://www.scopus.com/inward/record.url?scp=0036468255&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036468255&partnerID=8YFLogxK

M3 - Article

C2 - 11830527

AN - SCOPUS:0036468255

VL - 62

SP - 734

EP - 740

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 3

ER -

Keith RL, Miller YE, Hoshikawa Y, Moore MD, Gesell TL, Gao B et al. Manipulation of pulmonary prostacyclin synthase expression prevents murine lung cancer. Cancer Research. 2002 Feb 1;62(3):734-740.