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) E(2) 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-gamma (PPARgamma) 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 PPARgamma as a target of NSAID action in these cells. Overexpression of PPARgamma in NSCLC cells strongly inhibited the transformed growth properties of the cells, providing a molecular confirmation of the results obtained with the PPARgamma agonists. Increased expression of PPARgamma, 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 A(2), COX-1, or COX-2, sulindac sulfide and PPARgamma agonists also inhibited the transformed growth of these lung cancer cells. We propose that PPARgamma serves as a target for NSAIDs that accounts for COX-independent inhibition of lung cancer cell growth.