Increased PTEN expression due to transcriptional activation of PPARγ by Lovastatin and Rosiglitazone

Germline mutations in the tumor suppressor gene PTEN (protein phosphatase and tensin homolog located on chromosome ten) predispose to heritable breast cancer. The transcription factor PPAR gamma has also been implicated as a tumor suppressor pertinent to a range of neoplasias, including breast cancer. A putative PPAR gamma binding site in the PTEN promoter indicates that PPAR gamma may regulate PTEN expression. We show here that the PPAR gamma agonist Rosiglitazone, along with Lovastatin, induce PTEN in a dose- and time-dependent manner. Lovastatin- or Rosiglitazone-induced PTEN expression was accompanied by a decrease in phosphorylated-AKT and phosphorylated-MAPK and an increase in G1 arrest. We demonstrate that the mechanism of Lovastatin- and Rosiglitazone-associated PTEN expression was a result of an increase in PTEN mRNA, suggesting that this increase was transcriptionally-mediated. Compound-66, an inactive form of Rosiglitazone, which is incapable of activating PPARy, was unable to elicit the same response as Rosiglitazone, signifying that the Rosiglitazone response is PPAR gamma-mediated. To support this, we show, using reporter assays including dominant-negative constructs of PPAR gamma, that both Lovastatin and Rosiglitazone specifically mediate PPAR gamma activation. Additionally, we demonstrated that cells lacking PTEN or PPAR gamma were unable to induce PTEN mediated cellular events in the presence of Lovastatin or Rosiglitazone. These data are the first to demonstrate that Lovastatin can signal through PPAR gamma and directly demonstrate that PPAR gamma can upregulate PTEN at the transcriptional level. Since PTEN is constitutively active, our data indicates it may be worthwhile to examine Rosiglitazone and Lovastatin stimulation as mechanisms to increase PTEN expression for therapeutic and preventative strategies including cancer, diabetes mellitus and cardiovascular disease. (c) 2006 Wiley-Liss, Inc.