Epithelial-mesenchymal transition (EMT) was shown to confer tumor cells with abilities essential for metastasis, including migratory phenotype, invasiveness, resistance to apoptosis, evading immune surveillance, and tumor stem cell traits. Therefore, inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis. Here, we show that activation of peroxisome proliferator-activated receptor g (PPAR-g) inhibits transforming growth factor b (TGF-b)-induced EMT in lung cancer cells and prevents metastasis by antagonizing Smad3 function. Activation of PPAR-g by synthetic ligands (troglitazone and rosiglitazone) or by a constitutively active form of PPAR-g prevents TGF-b-induced loss of E-cadherin expression and inhibits the induction of mesenchymal markers (vimentin, N-cadherin, fibronectin) and matrix metalloproteases. Consistently, activation of PPAR-g also inhibited EMT-induced migration and invasion of lung cancer cells. Furthermore, effects of PPAR-g ligands were attenuated by siRNA-mediated knockdown of PPAR-g, indicating that the ligand-induced responses are PPAR-g dependent. Selective knockdown of Smad2 and Smad3 by siRNA showed that TGF-b-induced EMT is Smad3 dependent in lung cancer cells. Activation of PPAR-g inhibits TGF-b-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads. Consistently, PPAR-g activation prevented TGFb-induced transcriptional repression of E-cadherin promoter and inhibited transcriptional activation of Ncadherin promoter. Finally, treatment of mice with troglitazone or knockdown of Smad3 in tumor cells significantly inhibited TGF-b-induced experimental metastasis in SCID-Beige mice. Together, with the low toxicity profile of PPAR-g ligands, our data show that these ligands may serve as potential therapeutic agents to inhibit metastasis. Mol Cancer Ther; 9(12); 3221-32. Ó2010 AACR.

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Idiopathic pulmonary fibrosis (IPF) is a progressive and typically fatal lung disease for which no effective therapy has been identified. The disease is characterized by excessive collagen deposition, possibly in response to dysregulated wound healing. Mediators normally involved in would healing induce proliferation of fibroblasts and their differentiation to myofibroblasts that actively secrete collagen. Curcumin, a polyphenolic compound from turmeric, has been shown to exert a variety of biological effects. Effects on IPF and associated cell types remain unclear, however. We accordingly tested the ability of curcumin to inhibit proliferation and differentiation to myofibroblasts by human lung fibroblasts, including those from IPF patients. To further examine the potential usefulness of curcumin in IPF, we examined its ability to reduce fibrosis in bleomycin-treated mice. We show that curcumin effectively reduces profibrotic effects in both normal and IPF fibroblasts in vitro and that this reduction is accompanied by inhibition of key steps in the transforming growth factor-β (TGF-β) signaling pathway. In vivo, oral curcumin treatment showed no effect on important measures of bleomycin-induced injury in mice, whereas intraperitoneal curcumin administration effectively inhibited inflammation and collagen deposition along with a trend toward improved survival. Intraperitoneal curcumin reduced fibrotic progression even when administered after the acute bleomycin-induced inflammation had subsided. These results encourage further research on alternative formulations and routes of administration for this potentially attractive IPF therapy.