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

PPARβ/δ agonist stimulates human lung carcinoma cell growth through inhibition of PTEN... Recent studies suggest that activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) promotes cancer cell survival. We previously demonstrated that a selective PPARβ/δ agonist, GW501516 GenBank , stimulated human non-small cell lung carcinoma (NSCLC) cell growth. Here, we explore the mechanisms responsible for this effect. We show that GW501516 GenBank decreased phosphate and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor known to decrease cell growth and induce apoptosis. Activation of PPARβ/δ and phosphatidylinositol 3-kinase (PI3K)/Akt signaling was associated with inhibition of PTEN. GW501516 GenBank increased NF-κB DNA binding activity and p65 protein expression through activation of PPARβ/δ and PI3K/Akt signals and enhanced the physical interactions between PPARβ/δ and p65 protein. Conversely, inhibition of PI3K and silencing of p65 by small RNA interference (siRNA) blocked the effect of GW501516 GenBank on PTEN expression and on NSCLC cell proliferation. GW501516 GenBank also inhibited IKBα protein expression. Silencing of IKBα enhanced the effect of GW501516 GenBank on PTEN protein expression and on cell proliferation. It also augmented the GW501516 GenBank -induced complex formation of PPARβ/δ and p65 proteins. Overexpression of PTEN suppressed NSCLC cell growth and eliminated the effect of GW501516 GenBank on phosphorylation of Akt. Together, our observations suggest that GW501516 GenBank induces the proliferation of NSCLC cells by inhibiting the expression of PTEN through activation of PPARβ/δ, which stimulates PI3K/Akt and NF-κB signaling. Overexpression of PTEN overcomes this effect and unveils PPARβ/δ and PTEN as potential therapeutic targets in NSCLC. nuclear receptor; tumor suppressor; kinase signals; transcription factor; tumor cells Address for reprint requests and other correspondence: S. W. Han, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory Univ. School of Medicine, Whitehead Bioresearch Bldg., 615 Michael St., Suite 205-M, Atlanta, GA 30322 (e-mail: [email protected] ) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Lung Cellular and Molecular Physiology The American Physiological Society

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

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Publisher
The American Physiological Society
Copyright
Copyright © 2011 the American Physiological Society
ISSN
1040-0605
eISSN
1522-1504
DOI
10.1152/ajplung.00017.2008
pmid
18390835
Publisher site
See Article on Publisher Site

Abstract

Recent studies suggest that activation of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) promotes cancer cell survival. We previously demonstrated that a selective PPARβ/δ agonist, GW501516 GenBank , stimulated human non-small cell lung carcinoma (NSCLC) cell growth. Here, we explore the mechanisms responsible for this effect. We show that GW501516 GenBank decreased phosphate and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor known to decrease cell growth and induce apoptosis. Activation of PPARβ/δ and phosphatidylinositol 3-kinase (PI3K)/Akt signaling was associated with inhibition of PTEN. GW501516 GenBank increased NF-κB DNA binding activity and p65 protein expression through activation of PPARβ/δ and PI3K/Akt signals and enhanced the physical interactions between PPARβ/δ and p65 protein. Conversely, inhibition of PI3K and silencing of p65 by small RNA interference (siRNA) blocked the effect of GW501516 GenBank on PTEN expression and on NSCLC cell proliferation. GW501516 GenBank also inhibited IKBα protein expression. Silencing of IKBα enhanced the effect of GW501516 GenBank on PTEN protein expression and on cell proliferation. It also augmented the GW501516 GenBank -induced complex formation of PPARβ/δ and p65 proteins. Overexpression of PTEN suppressed NSCLC cell growth and eliminated the effect of GW501516 GenBank on phosphorylation of Akt. Together, our observations suggest that GW501516 GenBank induces the proliferation of NSCLC cells by inhibiting the expression of PTEN through activation of PPARβ/δ, which stimulates PI3K/Akt and NF-κB signaling. Overexpression of PTEN overcomes this effect and unveils PPARβ/δ and PTEN as potential therapeutic targets in NSCLC. nuclear receptor; tumor suppressor; kinase signals; transcription factor; tumor cells Address for reprint requests and other correspondence: S. W. Han, Division of Pulmonary, Allergy, and Critical Care Medicine, Emory Univ. School of Medicine, Whitehead Bioresearch Bldg., 615 Michael St., Suite 205-M, Atlanta, GA 30322 (e-mail: [email protected] )

Journal

AJP - Lung Cellular and Molecular Physiology – The American Physiological Society

Published: Jun 1, 2008

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