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 previously reported that PC-9ER cells acquire enhanced motility via TGF-β2-induced activation of the TGF-β/Smad2 pathway, which plays an important role in cell motility and migration.15,19 Therefore, we evaluated the effect of efatutazone on the transcription and secretion of TGF-β ligands. The basal mRNA levels of TGF-β2 in PC-9ER and PC-9ZD cells were higher than those in PC-9 cells. In contrast, no significant differences in the mRNA levels of TGF-β1 were observed among these cell lines (Fig. 2a). Efatutazone treatment suppressed TGF-β2 mRNA expression in all cells, whereas it did not suppress TGF-β1 mRNA expression (Fig. 2a). PC-9ER and PC-9ZD cells secreted significantly higher amounts of TGF-β2 than PC-9 cells did; however, PC-9ER and PC-9ZD cells did not secrete higher levels of TGF-β1 (Fig. 2b). Efatutazone significantly inhibited the secretion of TGF-β2 from all cells, confirming the effect of efatutazone on TGF-β2 transcription (Fig. 2b). These results indicate that efatutazone treatment significantly suppresses TGF-β2 secretion, by suppressing TGF-β2 mRNA expression.
Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.