Open AccessPeroxisome 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
Author(s) -
Serizawa Masakuni,
Murakami Haruyasu,
Watanabe Masaru,
Takahashi Toshiaki,
Yamamoto Nobuyuki,
Koh Yasuhiro
Publication year - 2014
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.12411
Subject(s) - cancer research , erlotinib , epidermal growth factor receptor , biology , protein kinase b , tyrosine kinase , growth factor receptor , transforming growth factor , signal transduction , endocrinology , receptor , microbiology and biotechnology , biochemistry
Epidermal growth factor receptor‐tyrosine kinase inhibitors ( EGFR ‐ TK I) are effective for non‐small cell lung cancers ( NSCLC ) with EGFR ‐activating mutations. However, most responders develop resistance. Efatutazone, a novel peroxisome proliferator‐activated receptor gamma ( PPAR γ) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation. The present study investigated the effects of efatutazone in EGFR ‐ TKI ‐resistant NSCLC cells, while focusing on cell motility. The PC ‐9‐derived NSCLC cell lines PC ‐9ER and PC ‐9ZD, resistant to EGFR ‐ TKI due to v‐crk avian sarcoma virus CT 10 oncogene homolog‐like ( CRKL ) amplification‐induced phosphatidylinositol 3‐kinase ( PI 3K)/v‐akt murine thymoma viral oncogene homolog ( AKT ) activation and an EGFR T790M mutation, respectively, were used. These cells exhibit enhanced cell motility due to transforming growth factor β ( TGF ‐β)/Smad2 family member 2 (Smad2) pathway activation. Efatutazone had no growth‐inhibitory effect on the tested cells but inhibited the motility of EGFR ‐ TK I‐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. Efatutazone suppressed increased TGF ‐β2 secretion from both cell lines (shown by ELISA ) and downregulation of TGF ‐β2 transcription (observed by quantitative RT ‐ PCR ). Immunoblot analysis and luciferase assays revealed that efatutazone suppressed Smad2 phosphorylation and its transcriptional activity. 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.