Ciglitazone induces early cellular proliferation and NF-κB transcriptional activity in colon cancer cells through p65 phosphorylation

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Abstract

While it is well established that peroxisome proliferator activated receptor γ (PPARγ) ligands inhibit cell growth and induce apoptosis of colon cancer cells with a prolonged treatment (3-5 days), the early effects of PPARγ exposure are less clear. In this report, we demonstrate that the PPARγ ligand, ciglitazone, induces proliferation of HT-29 and Caco-2 colon cancer cells transiently (<48 h) prior to a decrease in cell proliferation (>72 h). Associated with this cellular proliferation phase, we observed an increase in NF-κB transcriptional activity. Ciglitazone exposure did not affect NF-κB DNA binding but rather, increased phosphorylation of p65 as well as the recruitment of the co-activator CBP. Pre-treatment of HT-29 cells with wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, inhibited ciglitazone-induced p65 phosphorylation, NF-κB transcriptional activity and cell proliferation. Interestingly, ciglitazone inhibited PPAR transcriptional activity, suggesting this early proliferative effect is PPRE independent. These data suggest that the early proliferative phase of PPARγ ligand exposure is associated with activation of NF-κB by p65 phosphorylation and cofactor recruitment and not through increased DNA binding.

Original languageEnglish (US)
Pages (from-to)645-654
Number of pages10
JournalInternational Journal of Biochemistry and Cell Biology
Volume37
Issue number3
DOIs
StatePublished - Mar 1 2005
Externally publishedYes

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Peroxisome Proliferator-Activated Receptors
Phosphorylation
Colonic Neoplasms
Cells
Cell Proliferation
Ligands
Phosphatidylinositol 3-Kinase
HT29 Cells
DNA
Cell proliferation
Cell growth
Phosphotransferases
Chemical activation
ciglitazone
Apoptosis
Growth

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology

Cite this

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title = "Ciglitazone induces early cellular proliferation and NF-κB transcriptional activity in colon cancer cells through p65 phosphorylation",
abstract = "While it is well established that peroxisome proliferator activated receptor γ (PPARγ) ligands inhibit cell growth and induce apoptosis of colon cancer cells with a prolonged treatment (3-5 days), the early effects of PPARγ exposure are less clear. In this report, we demonstrate that the PPARγ ligand, ciglitazone, induces proliferation of HT-29 and Caco-2 colon cancer cells transiently (<48 h) prior to a decrease in cell proliferation (>72 h). Associated with this cellular proliferation phase, we observed an increase in NF-κB transcriptional activity. Ciglitazone exposure did not affect NF-κB DNA binding but rather, increased phosphorylation of p65 as well as the recruitment of the co-activator CBP. Pre-treatment of HT-29 cells with wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, inhibited ciglitazone-induced p65 phosphorylation, NF-κB transcriptional activity and cell proliferation. Interestingly, ciglitazone inhibited PPAR transcriptional activity, suggesting this early proliferative effect is PPRE independent. These data suggest that the early proliferative phase of PPARγ ligand exposure is associated with activation of NF-κB by p65 phosphorylation and cofactor recruitment and not through increased DNA binding.",
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AU - Chen, Fei

AU - Harrison, Lawrence

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N2 - While it is well established that peroxisome proliferator activated receptor γ (PPARγ) ligands inhibit cell growth and induce apoptosis of colon cancer cells with a prolonged treatment (3-5 days), the early effects of PPARγ exposure are less clear. In this report, we demonstrate that the PPARγ ligand, ciglitazone, induces proliferation of HT-29 and Caco-2 colon cancer cells transiently (<48 h) prior to a decrease in cell proliferation (>72 h). Associated with this cellular proliferation phase, we observed an increase in NF-κB transcriptional activity. Ciglitazone exposure did not affect NF-κB DNA binding but rather, increased phosphorylation of p65 as well as the recruitment of the co-activator CBP. Pre-treatment of HT-29 cells with wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, inhibited ciglitazone-induced p65 phosphorylation, NF-κB transcriptional activity and cell proliferation. Interestingly, ciglitazone inhibited PPAR transcriptional activity, suggesting this early proliferative effect is PPRE independent. These data suggest that the early proliferative phase of PPARγ ligand exposure is associated with activation of NF-κB by p65 phosphorylation and cofactor recruitment and not through increased DNA binding.

AB - While it is well established that peroxisome proliferator activated receptor γ (PPARγ) ligands inhibit cell growth and induce apoptosis of colon cancer cells with a prolonged treatment (3-5 days), the early effects of PPARγ exposure are less clear. In this report, we demonstrate that the PPARγ ligand, ciglitazone, induces proliferation of HT-29 and Caco-2 colon cancer cells transiently (<48 h) prior to a decrease in cell proliferation (>72 h). Associated with this cellular proliferation phase, we observed an increase in NF-κB transcriptional activity. Ciglitazone exposure did not affect NF-κB DNA binding but rather, increased phosphorylation of p65 as well as the recruitment of the co-activator CBP. Pre-treatment of HT-29 cells with wortmannin, a phosphatidylinositol 3-kinase (PI3K) kinase inhibitor, inhibited ciglitazone-induced p65 phosphorylation, NF-κB transcriptional activity and cell proliferation. Interestingly, ciglitazone inhibited PPAR transcriptional activity, suggesting this early proliferative effect is PPRE independent. These data suggest that the early proliferative phase of PPARγ ligand exposure is associated with activation of NF-κB by p65 phosphorylation and cofactor recruitment and not through increased DNA binding.

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