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Exp Cell Res. 2017 Dec 15;361(2):246-256. doi: 10.1016/j.yexcr.2017.10.024. Epub 2017 Oct 26.

PPARγ agonist efatutazone and gefitinib synergistically inhibit the proliferation of EGFR-TKI-resistant lung adenocarcinoma cells via the PPARγ/PTEN/Akt pathway.

Author information

1
Nanjing Medical University Affiliated Cancer Hospital, Department of Clinical Cancer Research Center, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China.
2
Department of Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China.
3
The Jiangsu Province Research Institute for Clinical Medicine, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
4
Department of Oncology, Yancheng First People's Hospital, Nanjing Medical University, Yancheng, Jiangsu, China.
5
Nanjing Medical University Affiliated Cancer Hospital, Department of Clinical Cancer Research Center, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, China. Electronic address: jifeng_feng@163.com.

Abstract

Development of acquired resistance to EGFR-TKI therapy continues to be a serious clinical problem in Lung adenocarcinoma management. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists demonstrate anti-tumor activity likely via transactivating genes that regulate cell proliferation, differentiation and apoptosis. Efatutazone, a novel later generation PPARγ agonist, selectively activates PPARγ target genes and has antiproliferative effects in a range of malignancies. However, the exact function and molecular mechanism of PPARγ agonists efatutazone in EGFR-TKI gefitinib-resistance of Lung adenocarcinoma has not been determined. In this study, we studied the development of acquired resistance to an EGFR-TKI gefitinib in lung adenocarcinoma cells and investigated the antiproliferative effects of efatutazone in the acquired resistant cells. The treatment of gefitinib-resistant cells with efatutazone reduced the growth of gefitinib-resistant cells in a dose- and time-dependent manner, and facilitated the anti-proliferative effects of gefitinib. Mechanistic investigations suggested that efatutazone acted by upregulating protein expression of PPARγ, phosphatase and tensin homolog (PTEN), inactivating the Akt pathway, followed by dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional levels. Our results suggested that efatutazone, alone or in combination with gefitinib, might offer therapeutic effects in lung adenocarcinoma.

KEYWORDS:

Efatutazone; Gefitinib resistance; Lung adenocarcinoma; PTEN; Peroxisome proliferator-activated receptor gamma

PMID:
29080795
DOI:
10.1016/j.yexcr.2017.10.024
[Indexed for MEDLINE]

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