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

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Date
2015-02
Authors
Chao, Ting-Ting
Wang, Cheng-Yi
Chen, Yen-Lin
Lai, Chih-Cheng
Chang, Fang-Yu
Tsai, Yi-Ting
Chao, Chung-Hao H
Shiau, Chung-Wai
Huang, Yuh-Chin T
Yu, Chong-Jen
Chen, Kuen-Feng
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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.
Type
Journal article
Subject
Cell Line, Tumor
Animals
Humans
Mice, Nude
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Quinazolines
Intracellular Signaling Peptides and Proteins
Membrane Proteins
Autoantigens
Xenograft Model Antitumor Assays
Reverse Transcriptase Polymerase Chain Reaction
Apoptosis
Gene Expression Regulation, Neoplastic
RNA Interference
Protein Binding
Mutation
Aged
Middle Aged
Female
Male
ets-Domain Protein Elk-1
Proto-Oncogene Proteins c-akt
Protein Phosphatase 2
Promoter Regions, Genetic
Kaplan-Meier Estimate
ErbB Receptors
Afatinib
Permalink
https://hdl.handle.net/10161/22245
Published Version (Please cite this version)
10.18632/oncotarget.2941
Publication Info
Chao, Ting-Ting; Wang, Cheng-Yi; Chen, Yen-Lin; Lai, Chih-Cheng; Chang, Fang-Yu; Tsai, Yi-Ting; ... Chen, Kuen-Feng (2015). Afatinib induces apoptosis in NSCLC without EGFR mutation through Elk-1-mediated suppression of CIP2A. Oncotarget, 6(4). pp. 2164-2179. 10.18632/oncotarget.2941. Retrieved from https://hdl.handle.net/10161/22245.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Huang

Yuh-Chin Tony Huang

Professor of Medicine
Closed loop ventilation Environmental medicine Oxidative lung injuryCOPDHyperpolarized 129Xe MRI and regional lung function
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