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Peroxisome proliferator-activated receptor γ agonist efatutazone impairs transforming growth factor β2-induced motility of epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer cells.

Serizawa M, Murakami H, Watanabe M, Takahashi T, Yamamoto N, Koh Y - Cancer Sci. (2014)

Bottom Line: Efatutazone, a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation.Efatutazone had no growth-inhibitory effect on the tested cells but inhibited the motility of EGFR-TKI-resistant cells in wound closure and transwell assays.Efatutazone plus erlotinib treatment provided greater inhibition of PC-9ER cell migration than efatutazone or erlotinib alone.

View Article: PubMed Central - PubMed

Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.

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Effect of efatutazone treatment on molecules relevant to the transforming growth factor β (TGF-β), epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. (a) The effect of erlotinib and/or efatutazone on relevant molecules was evaluated by immunoblot analysis. Cells were incubated for 48 h in FBS-free medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L) or a combination of erlotinib and efatutazone. The cells were lysed, and the indicated proteins were detected by immunoblotting. (b) The effect of efatutazone on Smad-mediated transcriptional activity was evaluated by using a luciferase reporter assay. After the cells were transfected with the Smad-dependent reporter p3TP-Lux, they were incubated for 24 h in FBS-free medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. The values were normalized relative to the Renilla luciferase activity in cells cotransfected with pRL-CMV. *P < 0.05; **P < 0.01; ***P < 0.001 (Student's t-test). The error bars indicate the standard deviations of the mean.
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fig03: Effect of efatutazone treatment on molecules relevant to the transforming growth factor β (TGF-β), epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. (a) The effect of erlotinib and/or efatutazone on relevant molecules was evaluated by immunoblot analysis. Cells were incubated for 48 h in FBS-free medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L) or a combination of erlotinib and efatutazone. The cells were lysed, and the indicated proteins were detected by immunoblotting. (b) The effect of efatutazone on Smad-mediated transcriptional activity was evaluated by using a luciferase reporter assay. After the cells were transfected with the Smad-dependent reporter p3TP-Lux, they were incubated for 24 h in FBS-free medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. The values were normalized relative to the Renilla luciferase activity in cells cotransfected with pRL-CMV. *P < 0.05; **P < 0.01; ***P < 0.001 (Student's t-test). The error bars indicate the standard deviations of the mean.

Mentions: We next examined the effect of efatutazone on the activity of Smad2, which is a key downstream effector of the TGF-β pathway. Elevated phosphorylation of Smad2 and enhanced Smad2-mediated transcriptional activity were observed in both PC-9ER and PC-9ZD cells (Figs. 3a,b and Fig. S3). Efatutazone suppressed the elevated phosphorylation of Smad2 in both PC-9ER and PC-9ZD cells (Fig. 3a and Fig. S3). Efatutazone treatment also significantly decreased subsequent Smad-mediated transcriptional regulatory activity in all cells (Fig. 3b), indicating that suppression of TGF-β2 expression by efatutazone abrogates activation of the TGF-β/Smad2 pathway. These observations suggest TGF-β2-mediated cross-talk between PPARγ and the TGF-β pathway.


Peroxisome proliferator-activated receptor γ agonist efatutazone impairs transforming growth factor β2-induced motility of epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer cells.

Serizawa M, Murakami H, Watanabe M, Takahashi T, Yamamoto N, Koh Y - Cancer Sci. (2014)

Effect of efatutazone treatment on molecules relevant to the transforming growth factor β (TGF-β), epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. (a) The effect of erlotinib and/or efatutazone on relevant molecules was evaluated by immunoblot analysis. Cells were incubated for 48 h in FBS-free medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L) or a combination of erlotinib and efatutazone. The cells were lysed, and the indicated proteins were detected by immunoblotting. (b) The effect of efatutazone on Smad-mediated transcriptional activity was evaluated by using a luciferase reporter assay. After the cells were transfected with the Smad-dependent reporter p3TP-Lux, they were incubated for 24 h in FBS-free medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. The values were normalized relative to the Renilla luciferase activity in cells cotransfected with pRL-CMV. *P < 0.05; **P < 0.01; ***P < 0.001 (Student's t-test). The error bars indicate the standard deviations of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig03: Effect of efatutazone treatment on molecules relevant to the transforming growth factor β (TGF-β), epidermal growth factor receptor (EGFR) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. (a) The effect of erlotinib and/or efatutazone on relevant molecules was evaluated by immunoblot analysis. Cells were incubated for 48 h in FBS-free medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L) or a combination of erlotinib and efatutazone. The cells were lysed, and the indicated proteins were detected by immunoblotting. (b) The effect of efatutazone on Smad-mediated transcriptional activity was evaluated by using a luciferase reporter assay. After the cells were transfected with the Smad-dependent reporter p3TP-Lux, they were incubated for 24 h in FBS-free medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. The values were normalized relative to the Renilla luciferase activity in cells cotransfected with pRL-CMV. *P < 0.05; **P < 0.01; ***P < 0.001 (Student's t-test). The error bars indicate the standard deviations of the mean.
Mentions: We next examined the effect of efatutazone on the activity of Smad2, which is a key downstream effector of the TGF-β pathway. Elevated phosphorylation of Smad2 and enhanced Smad2-mediated transcriptional activity were observed in both PC-9ER and PC-9ZD cells (Figs. 3a,b and Fig. S3). Efatutazone suppressed the elevated phosphorylation of Smad2 in both PC-9ER and PC-9ZD cells (Fig. 3a and Fig. S3). Efatutazone treatment also significantly decreased subsequent Smad-mediated transcriptional regulatory activity in all cells (Fig. 3b), indicating that suppression of TGF-β2 expression by efatutazone abrogates activation of the TGF-β/Smad2 pathway. These observations suggest TGF-β2-mediated cross-talk between PPARγ and the TGF-β pathway.

Bottom Line: Efatutazone, a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation.Efatutazone had no growth-inhibitory effect on the tested cells but inhibited the motility of EGFR-TKI-resistant cells in wound closure and transwell assays.Efatutazone plus erlotinib treatment provided greater inhibition of PC-9ER cell migration than efatutazone or erlotinib alone.

View Article: PubMed Central - PubMed

Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.

Show MeSH
Related in: MedlinePlus