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Vol. 62, Issue 5, 1207-1214, November 2002
Is a Target of
Nonsteroidal Anti-Inflammatory Drugs Mediating
Cyclooxygenase-Independent Inhibition of Lung Cancer Cell Growth
Department of Medicine, University of Colorado Health Science
Center, Denver, Colorado
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the growth of
different cancer cell types, suggesting a broad role for their
cyclooxygenase (COX) targets and eicosanoid products in tumor cell
growth. Sulindac sulfide, a COX inhibitor, inhibited the growth of
non-small-cell lung cancers (NSCLC) both in soft agar and as
xenografts in nude mice. Importantly, the concentration of sulindac
sulfide required to inhibit NSCLC cell growth greatly exceeded the
concentration required to inhibit prostaglandin (PG) E2
synthesis in NSCLC cells, suggesting that NSAID inhibition of cell
growth is mediated by additional targets distinct from COX. Both
sulindac sulfide and ciglitazone, a defined peroxisome proliferator-activated receptor-
(PPAR) agonist, stimulated a
promoter construct containing a PPAR response element linked to
luciferase and potently inhibited NSCLC cell growth at similar concentrations, indicating a role for PPAR as a target of NSAID action in these cells. Overexpression of PPAR in NSCLC cells strongly inhibited the transformed growth properties of the cells, providing a molecular confirmation of the results obtained with the
PPAR agonists. Increased expression of PPAR, as well as ciglitazone and sulindac sulfide induced expression of E-cadherin, which has been linked to increased differentiation of NSCLC. Despite the fact that SCLC cell lines expressed little or no cytosolic phospholipase A2, COX-1, or COX-2, sulindac sulfide and
PPAR agonists also inhibited the transformed growth of these lung
cancer cells. We propose that PPAR serves as a target for NSAIDs
that accounts for COX-independent inhibition of lung cancer cell growth.
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