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Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A

Ting-Ting Chao, Cheng-Yi Wang, Yen-Lin Chen, Chih-Cheng Lai, Fang-Yu Chang, Yi-Ting Tsai, Chung-Hao H. Chao, Chung-Wai Shiau, Yuh-Chin T. Huang, Chong-Jen Yu _ and Kuen-Feng Chen

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Oncotarget. 2015; 6:2164-2179. https://doi.org/10.18632/oncotarget.2941

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Abstract

Ting-Ting Chao1,*, Cheng-Yi Wang1,2,3,*, Yen-Lin Chen4, Chih-Cheng Lai5, Fang-Yu Chang1, Yi-Ting Tsai1, Chung-Hao H. Chao6, Chung-Wai Shiau7, Yuh-Chin T. Huang8, Chong-Jen Yu9 and Kuen-Feng Chen10,11

1 Medical Research Center, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan

2 Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan

3 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

4 Department of Pathology, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan

5 Department of Intensive Care Medicine, Chi Mei Medical Center, Liouying, Tainan, Taiwan

6 Instrumentation Resource Center, National Yang-Ming University, Taipei, Taiwan

7 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan

8 Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA

9 Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan

10 Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

11 National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan

* These authors contributed equally to this work

Correspondence:

Chong-Jen Yu, email:

Kuen-Feng Chen, email:

Keywords: CIP2A, EGFR, PP2A, Elk-1, afatinib

Received: August 05, 2014 Accepted: December 10, 2014 Published: December 11, 2014

Abstract

Afatinib has anti-tumor effect in non-small cell lung carcinoma (NSCLC) with epidermal growth factor receptor (EGFR) mutation. We found afatinib can also induce apoptosis in NSCLC cells without EGFR mutation through CIP2A pathway. Four NSCLC cell lines (H358 H441 H460 and A549) were treated with afatinib to determine their sensitivity to afatinib-induced cell death and apoptosis. The effects of CIP2A on afatinib-induced apoptosis were confirmed by overexpression and knockdown of CIP2A expression in the sensitive and resistant cells, respectively. Reduction of Elk-1 binding to the CIP2A promoter and suppression of CIP2A transcription were analyzed. In vivo efficacy of afatinib against H358 and H460 xenografts tumors were also determined in nude mice. Afatinib induced significant cell death and apoptosis in H358 and H441 cells, but not in H460 or A549 cells. The apoptotic effect of afatinib in sensitive cells was associated with downregulation of CIP2A, promotion of PP2A activity and decrease in AKT phosphorylation. Afatinib suppressed CIP2A at the gene transcription level by reducing the promoter binding activity of Elk-1. Clinical samples showed that higher CIP2A expression predicted a poor prognosis and Elk-1 and CIP2A expressions were highly correlated. In conclusion, afatinib induces apoptosis in NSCLC without EGFR mutations through Elk-1/CIP2A/PP2A/AKT pathway.


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