Open AccessDepleted aldehyde dehydrogenase 1 A 1 ( ALDH1A1 ) reverses cisplatin resistance of human lung adenocarcinoma cell A 549/ DDP
Author(s) -
Wei Yunyan,
Wu Shuangshuang,
Xu Wei,
Liang Yan,
Li Yue,
Zhao Weihong,
Wu Jianqing
Publication year - 2017
Publication title -
thoracic cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.823
H-Index - 28
eISSN - 1759-7714
pISSN - 1759-7706
DOI - 10.1111/1759-7714.12400
Subject(s) - cisplatin , a549 cell , protein kinase b , cancer research , viability assay , pi3k/akt/mtor pathway , apoptosis , medicine , microbiology and biotechnology , lung cancer , chemistry , biology , oncology , biochemistry , chemotherapy
Background Cisplatin is the standard first‐line chemotherapeutic agent for the treatment of non‐small cell lung cancer (NSCLC). However, resistance to chemotherapy has been a major obstacle in the management of NSCLC. Aldehyde dehydrogenase 1A1 (ALDH1A1) overexpression has been observed in a variety of cancers, including lung cancer. The purpose of this study was to investigate the effect of ALDH1A1 expression on cisplatin resistance and explore the mechanism responsible. Methods Reverse transcriptase‐PCR was applied to measure the messenger RNA expression of ALDH1A1, while Western blot assay was employed to evaluate the protein expression of ALDH1A 1, B ‐cell lymphoma 2, B cl‐2‐like protein 4, phospho‐protein kinase B (p‐ AKT) and AKT . A short hairpin RNA was used to knockdown ALDH1A 1 expression. A 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay was used to determine the effect of ALDH1A 1 decrease on cell viability. The cell apoptotic rate was tested using flow cytometry assay. Results ALDH1A 1 is overexpressed in cisplatin resistant cell line A549/DDP , compared with A 549. ALDH1A1 depletion significantly decreased A 549/ DDP proliferation, increased apoptosis, and reduced cisplatin resistance. In addition, the phosphoinositide 3‐kinase (PI 3 K) / AKT pathway is activated in A 549/ DDP , and ALDH 1 A 1 knockdown reduced the phosphorylation level of AKT . Moreover, the combination of ALDH1A1 ‐short hairpin RNA and PI 3 K / AKT pathway inhibitor LY 294002 markedly inhibited cell viability, enhanced apoptotic cell death, and increased cisplatin sensitivity. Conclusion These results suggest that ALDH1A1 depletion could reverse cisplatin resistance in human lung cancer cell line A 549/ DDP , and may act as a potential target for the treatment of lung cancers resistant to cisplatin.