Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 1 de 1
Filter
Add more filters











Database
Language
Publication year range
1.
Oncotarget ; 6(4): 2164-79, 2015 Feb 10.
Article in English | MEDLINE | ID: mdl-25537503

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.


Subject(s)
Apoptosis/drug effects , Autoantigens/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Membrane Proteins/genetics , Quinazolines/pharmacology , ets-Domain Protein Elk-1/genetics , Afatinib , Aged , Animals , Autoantigens/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Cell Line, Tumor , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , Intracellular Signaling Peptides and Proteins , Kaplan-Meier Estimate , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Male , Membrane Proteins/metabolism , Mice, Nude , Middle Aged , Mutation , Promoter Regions, Genetic/genetics , Protein Binding/drug effects , Protein Phosphatase 2/genetics , Protein Phosphatase 2/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Xenograft Model Antitumor Assays , ets-Domain Protein Elk-1/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL