PPARγ agonist efatutazone and gefitinib synergistically inhibit the proliferation of EGFR-TKI-resistant lung adenocarcinoma cells via the PPARγ/PTEN/Akt pathway
PPARγ agonist efatutazone and gefitinib synergistically inhibit the proliferation of EGFR-TKI-resistant lung adenocarcinoma cells via the PPARγ/PTEN/Akt pathway
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DOI：
10.1016/j.yexcr.2017.10.024
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发表时间：
2017-12-15
影响因子：
3.7
通讯作者：
Feng, Jifeng
中科院分区：
文献类型：
--
作者：
Ni, Jie;Zhou, Lei-lei;Feng, Jifeng
对EGFR-TKI治疗的获得性耐药的发展仍然是肺腺癌治疗中的一个严重临床问题。过氧化物酶体增殖物激活受体γ（PPAR γ）激动剂显示抗肿瘤活性，其可能通过调节细胞增殖、分化和凋亡的反式激活基因来实现。Efatutazone是一种新型的新一代PPARy激动剂，选择性激活PPARy靶基因，并在一系列恶性肿瘤中具有抗增殖作用。然而，尚未确定PPARy激动剂依法他宗在肺腺癌的EGFR-TKI吉非替尼抗性中的确切功能和分子机制。在这项研究中，我们研究了肺腺癌细胞对EGFR-TKI吉非替尼获得性耐药的发展，并研究了afatutazone在获得性耐药细胞中的抗增殖作用。吉非替尼耐药细胞的efatutazone治疗减少吉非替尼耐药细胞的生长在剂量和时间依赖性的方式，并促进吉非替尼的抗增殖作用。机制研究表明，efatutazone通过上调蛋白质表达的PPARy，磷酸酶和张力蛋白同源物（PTEN），失活Akt通路，然后通过去磷酸化的p21 Cip 1在Thr 145不影响转录水平。我们的研究结果表明，efatutazone，单独或与吉非替尼，可能会提供肺腺癌的治疗效果。
Development of acquired resistance to EGFR-TKI therapy continues to be a serious clinical problem in Lung adenocarcinoma management. Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists demonstrate anti-tumor activity likely via transactivating genes that regulate cell proliferation, differentiation and apoptosis. Efatutazone, a novel later generation PPARy agonist, selectively activates PPARy target genes and has anti proliferative effects in a range of malignancies. However, the exact function and molecular mechanism of PPARy 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 PPARy, 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.