Inhibition of autophagy enhances effects of PF-04691502 on apoptosis and DNA damage of lung cancer cells.

Autor: Fei HR; School of Pharmacology, Taishan Medical University, Taian 271016, PR China., Tian H; Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China., Zhou XL; Public R&D Center of Bio-Manufacture, Hebei University of Science and Technology, Shijiazhuang, 050000, PR China., Yang MF; Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China., Sun BL; Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China., Yang XY; Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China. Electronic address: xyyang@tsmc.edu.cn., Jiao P; Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China. Electronic address: jiaopeng196@163.com., Wang FZ; Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China; School of Life Sciences, Taishan Medical University, Taian, 271016, PR China. Electronic address: fengzewang@gmail.com.
Jazyk: angličtina
Zdroj: The international journal of biochemistry & cell biology [Int J Biochem Cell Biol] 2016 Sep; Vol. 78, pp. 52-62. Date of Electronic Publication: 2016 Jul 01.
DOI: 10.1016/j.biocel.2016.06.023
Abstrakt: Autophagy modulation has been considered as a potential therapeutic strategy for lung diseases. The PI3K-Akt-mTOR pathway may be one of the main targets for regulation of autophagy. We previously reported that a PI3K/mTOR dual inhibitor PF-04691502 suppressed hepatoma cells growth in vitro. However, it is still unclear whether PF-04691502 induces autophagy and its roles in DNA damage and cell death in human lung cancer cells. In this study, we investigate the effects of PF-04691502 on the autophagy and its correlation with cell apoptosis and DNA damage in non-small-cell lung cancer (NSCLC) cell lines. PF-04691502 efficiently inhibited the phosphorylation of Akt and showed dose-dependent cytotoxicity in A549 and H1299 cells. PF-04691502 also triggered apoptosis and the cleavage of caspase-3 and PARP. Phosphorylated histone H2AX (γ-H2AX), a hallmark of DNA damage response, was dramatically induced by PF-04691502 treatment. By exposure to PF-04691502, A549 cells acquired a senescent-like phenotype with an increase in the level of β-galactosidase. Furthermore, PF-04691502 enhanced the expression of LC3-II in a concentration-dependent manner. More interestingly, effects of PF-04691502 on toxicity and DNA damage were remarkably increased by co-treatment with an autophagy inhibitor, chloroquine (CQ), in human lung cancer cells. These data suggest that a strategy of blocking autophagy to enhance the activity of PI3K/mTOR inhibitors warrants further attention in treatment of NSCLC cells.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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