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.
Bottom Line: 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.These results suggest that efatutazone inhibits cell motility by antagonizing the TGF-β/Smad2 pathway and effectively prevents metastasis in NSCLC patients with acquired resistance to EGFR-TKI regardless of the resistance mechanism.
Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.Show MeSH
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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.
Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.