title: Inhibition of autophagy enhances effects of PF-04691502 on apoptosis and DNA damage of lung cancer cells.
abstract: 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.
authors.affiliation: School of Pharmacology, Taishan Medical University, Taian 271016, PR China.
authors.forename: Hong-Rong
authors.initials: HR
authors.lastname: Fei
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China.
authors.forename: Hua-
authors.initials: H
authors.lastname: Tian
authors.affiliation: Public R&D Center of Bio-Manufacture, Hebei University of Science and Technology, Shijiazhuang, 050000, PR China.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China.
authors.forename: Ming-Feng
authors.initials: MF
authors.lastname: Yang
authors.affiliation: Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China.
authors.forename: Bao-Liang
authors.initials: BL
authors.lastname: Sun
authors.affiliation: Key Laboratory of Brain Microcirculation in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China. Electronic address: xyyang@tsmc.edu.cn.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Key Laboratory of Atherosclerosis in Universities of Shandong, Taishan Medical University, Taian, 271000, PR China. Electronic address: jiaopeng196@163.com.
authors.forename: Peng-
authors.initials: P
authors.lastname: Jiao
authors.affiliation: 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.
authors.forename: Feng-Ze
authors.initials: FZ
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; D011728:Pyridones; D011743:Pyrimidines; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; Autophagy; DNA damage; PF-04691502; PI3K/mTOR