The Role of PPARgamma in the Cyclooxygenase Pathway in Lung Cancer.
Decreased expression of peroxisome proliferator activated receptor-gamma (PPARgamma) and high levels of the proinflammatory enzyme cyclooxygenase-2 (COX-2) have been observed in many tumor types. Both reduced (PPARgamma) expression and elevated COX-2 within the tumor are associated with poor prognosis in lung cancer patients, and recent work has indicated that these signaling pathways may be interrelated. Synthetic (PPARgamma) agonists such as the thiazolidinedione (TZD) class of anti-diabetic drugs can decrease COX-2 levels, inhibit growth of non-small-cell lung cancer (NSCLC) cells in vitro, and block tumor progression in xenograft models. TZDs alter the expression of COX-2 and consequent production of the protumorigenic inflammatory molecule prostaglandin E2 (PGE2) through both (PPARgamma) dependent and independent mechanisms. Certain TZDs also reduce expression of PGE2 receptors or upregulate the PGE2 catabolic enzyme 15-prostaglandin dehydrogenase. As several COX-2 enzymatic products have antitumor properties and specific COX-2 inhibition has been associated with increased risk of adverse cardiac events, directly reducing the effects or concentration of PGE2 may provide a more safe and effective strategy for lung cancer treatment. Understanding the mechanisms underlying these effects may be helpful for designing anticancer therapies. This article summarizes recent research on the relationship between (PPARgamma), TZDs, and the COX-2/PGE2 pathways in lung cancer.
Hazra
Saswati
S
UCLA Lung Cancer Research Program, Division of Pulmonary and Critical Care Medicine and Hospitalists, Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Peebles
Katherine A
KA
Sharma
Sherven
S
Mao
Jenny T
JT
Dubinett
Steven M
SM