Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 294, Issue 6, Pages L1238-L1249Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00017.2008
Keywords
nuclear receptor; tumor suppressor; kinase signals; transcription factor; tumor cells
Categories
Ask authors/readers for more resources
Recent studies suggest that activation of peroxisome proliferator-activated receptor beta/delta ( PPAR beta/delta) promotes cancer cell survival. We previously demonstrated that a selective PPAR beta/delta 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 PPAR beta/delta and phosphatidylinositol 3-kinase (PI3K)/Akt signaling was associated with inhibition of PTEN. GW501516 increased NF-kappa B DNA binding activity and p65 protein expression through activation of PPAR beta/delta and PI3K/Akt signals and enhanced the physical interactions between PPAR beta/delta 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 alpha protein expression. Silencing of IKB alpha enhanced the effect of GW501516 on PTEN protein expression and on cell proliferation. It also augmented the GW501516-induced complex formation of PPAR beta/delta 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 PPAR beta/delta, which stimulates PI3K/Akt and NF-kappa B signaling. Overexpression of PTEN overcomes this effect and unveils PPAR beta/delta and PTEN as potential therapeutic targets in NSCLC.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available