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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/L1238    most recent 00017.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Han, S. Articles by Roman, J. PubMed PubMed Citation Articles by Han, S. Articles by Roman, J.

PPARβ/ agonist stimulates human lung carcinoma cell growth through inhibition of PTEN expression: the involvement of PI3K and NF-B signals

¹Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; ²Department of Obstetrics and Gynecology, West China 2nd University Hospital, Sichuan University, Chengdu, China; and ³Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

Submitted 9 January 2008 ; accepted in final form 4 April 2008

Recent studies suggest that activation of peroxisome proliferator-activated receptor β/ (PPARβ/) promotes cancer cell survival. We previously demonstrated that a selective PPARβ/ agonist, GW501516, stimulated human non-small cell lung carcinoma (NSCLC) cell growth. Here, we explore the mechanisms responsible for this effect. We show that GW501516 decreased phosphate and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor known to decrease cell growth and induce apoptosis. Activation of PPARβ/ and phosphatidylinositol 3-kinase (PI3K)/Akt signaling was associated with inhibition of PTEN. GW501516 increased NF-B DNA binding activity and p65 protein expression through activation of PPARβ/ and PI3K/Akt signals and enhanced the physical interactions between PPARβ/ and p65 protein. Conversely, inhibition of PI3K and silencing of p65 by small RNA interference (siRNA) blocked the effect of GW501516 on PTEN expression and on NSCLC cell proliferation. GW501516 also inhibited IKB protein expression. Silencing of IKB enhanced the effect of GW501516 on PTEN protein expression and on cell proliferation. It also augmented the GW501516-induced complex formation of PPARβ/ and p65 proteins. Overexpression of PTEN suppressed NSCLC cell growth and eliminated the effect of GW501516 on phosphorylation of Akt. Together, our observations suggest that GW501516 induces the proliferation of NSCLC cells by inhibiting the expression of PTEN through activation of PPARβ/, which stimulates PI3K/Akt and NF-B signaling. Overexpression of PTEN overcomes this effect and unveils PPARβ/ and PTEN as potential therapeutic targets in NSCLC.

nuclear receptor; tumor suppressor; kinase signals; transcription factor; tumor cells