The ligand-activated nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) has been shown to regulate differentiation, survival, lipid metabolism, tissue repair, energy homeostasis, proliferation, and/or apoptosis. Recent studies suggest that activation of PPARβ/δ is involved in tumor cell growth. We previously demonstrated that a PPARβ/δ agonist, GW501516 inhibited the expression the tumor suppressor PTEN in human non-small cell lung carcinoma (NSCLC) cells. Here, we explore the cellular mechanism(s) that mediate this effect. Our results show that treatment with a selective PPARβ/δ agonist, GW501516 decreased PTEN protein and mRNA expression that was not affected in the presence of PPARβ/δ siRNA indicating the involvement of PPARβ/δ-independent signals. Additionally, we observed that GW501516 increased the DNA binding activity of NF-κB and increased the NF-κB subunit p65 protein, while it reduced IKBα protein expression in NSCLC. The p65 siRNA blocked the effect of GW501516 on PTEN expression and on NSCLC cell proliferation. Finally, adenoviral-mediated transfer of PTEN (Ad-PTEN) inhibited cell growth and diminished the effects of GW501516. Taken together, our observations suggest that a PPARβ/δ agonist, GW501516 induces the proliferation of NSCLC cells by inhibiting the expression of PTEN through activation of NF-κB that is independent of PPARβ/δ activation. Overexpression of PTEN may provide a potential therapeutic strategy for lung cancer treatment.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]