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A FASN-TGF-β1-FASN regulatory loop contributes to high EMT/metastatic potential of cisplatin-resistant non-small cell lung cancer

Li Yang, Fuquan Zhang, Xin Wang, Ying Tsai, Kuang-Hsiang Chuang, Peter C. Keng, Soo Ok Lee and Yuhchyau Chen _

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Oncotarget. 2016; 7:55543-55554. https://doi.org/10.18632/oncotarget.10837

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Abstract

Li Yang1, Fuquan Zhang1, Xin Wang1, Ying Tsai1, Kuang-Hsiang Chuang1, Peter C. Keng1, Soo Ok Lee1, Yuhchyau Chen1

1Department of Radiation Oncology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA

Correspondence to:

Yuhchyau Chen, email: Yuhchyau_Chen@urmc.rochester.edu

Soo Ok Lee, email: Soook_Lee@urmc.rochester.edu

Keywords: non-small cell lung cancer, EMT, cisplatin-resistance, fatty acid synthase (FASN), TGF-β1

Received: May 04, 2016    Accepted: July 11, 2016    Published: July 25, 2016

ABSTRACT

Cisplatin-resistant A549CisR and H157CisR cell lines were developed by treating parental A549 (A549P) and H157 (H157P) cells. These cisplatin-resistant cells showed slight growth retardation, but exhibited higher epithelial-mesenchymal transition (EMT) and increased metastatic potential compared to parental cells. We observed a highly up-regulated fatty acid synthase (FASN) level in A549CisR and H157CisR cells compared to parental cells and the up-regulation of FASN was also detected in A549P and H157P cells after short time treatment with cisplatin, suggesting that the high level of FASN in cisplatin-resistant cells may be from the accumulated cellular responses during cisplatin-resistance developmental process. We next investigated whether the inhibition of FASN by using a specific FASN inhibitor, cerulenin, can influence growth and EMT/metastatic potential of A549CisR and H157CisR cells. There was slight growth inhibition, but significantly reduced EMT/metastatic potential in cisplatin-resistant cells upon inhibitor treatment. The in vitro result was further investigated in orthotopic xenograft mouse models established with luciferase-tagged H157P and H157CisR cells. Mice were injected with cerulenin or vehicle after tumors were developed. No significant tumor regression was detected at the end of cerulenin treatment, but IHC staining showed higher expression of EMT/metastasis markers in H157CisR cell-derived tumors than H157P cell-derived tumors, and showed dramatic reduction of these markers in tumor tissues of cerulenin-treated mice, confirming the in vitro results. In mechanism dissection studies, we revealed the existence of the FASN-TGF-β1-FASN positive loop in A549CisR and H157CisR cells, but not in parental cells, which is believed to augment the FASN function in cisplatin-resistant cells.


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