期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 120, 期 1, 页码 756-767出版社
WILEY
DOI: 10.1002/jcb.27434
关键词
autophagy; AZD9291; epidermal growth factor receptor (EGFR); phosphoinositide-3 kinase/protein kinase B (PI3K/Akt)
资金
- Education Department of Anhui Natural Science Research Project China [KJ2018A0238]
- Key development project of Jiangsu Province [BE2017712]
- Open Project Program of Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica [JKLPSE201509]
- Six talent peaks project in Jiangsu Province [YY-012]
- Natural Science Fund of China [91540119, 81473293, 81673462, 31071250]
- Fundamental Research Funds for the Central Universities
- Priority Academic Program Development of Jiangsu Higher Education Institutions
AZD9291, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is highly selective against EGFR T790M-mutant non-small cell lung cancer (NSCLC). On investigating the growth inhibitory effects of AZD9291 on NSCLC and the underlying mechanism, we found that AZD9291 can trigger autophagy-mediated cell death in both A549 and H1975 cells by increasing the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3) and decreasing the expression of p62. In the presence of the autophagy inhibitor chloroquine, the AZD9291-induced increase in LC3 level was further augmented. AZD9291 decreased the levels of phosphoinositide-3 kinase (PI3K), protein kinase B (Akt), and phosphorylated Akt. AZD9291-induced cell death was enhanced by Akt knockdown, and the levels of both EGFR and phosphorylated EGFR were decreased by AZD9291. AZD9291 was also found to significantly suppress the tumor growth in H1975 xenograft nude mice. Thus, AZD9291 was found to induce autophagy, decrease in EGFR levels, and show a strong inhibitory effect on NSCLC both in vitro and in vivo. Furthermore, the PI3K/Akt signaling pathway was found to play a critical role in AZD9291-induced cell death.
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