title: The p70S6K Specific Inhibitor PF-4708671 Impedes Non-Small Cell Lung Cancer Growth.
abstract: BACKGROUND
  As a serine/threonine protein kinase, p70S6K plays an important role in tumor cells. Evidence has revealed overexpression of p70S6K and phosphorylated p70S6K (p-p70S6K) in various tumor tissues, with these proteins identified as independent prognostic markers in non-small cell lung cancer (NSCLC). In this study, we explored the role of the p70S6K specific inhibitor PF-4708671 in NSCLC.
  
  
  METHODS
  Three NSCLC cell lines (A549, SK-MES-1, and NCI-H460) were treated with PF-4708671 at five different concentrations, including 0.1μM, 0.3μM, 1μM, 3μM and 10μM, and protein levels were determined by Western-blot. Then, PF-4708671's effects were assessed both in vitro (cell proliferation, apoptosis, cell cycle distribution, and invasion) and in vivo.
  
  
  RESULTS
  The expression levels of p-p70S6K and the downstream effector S6 were significantly reduced by PF-4708671. Diametrically opposite, the downstream protein levels of BAD, Caspase3 and ERK had increased after treatment with PF-4708671. In addition, PF-4708671 drastically inhibited cell proliferation and invasion ability in A549, SK-MES-1 and NCI-H460 cells in vitro, causing cell cycle arrest in G0-G1 phase. Limited effects of PF-4708671 were observed on apoptosis in the three NSCLC cell lines assessed. Importantly, PF-4708671 could inhibit tumorigenesis in nude mice in vivo.
  
  
  CONCLUSIONS
  These findings demonstrated that the p70S6K specific inhibitor PF-4708671 has inhibitory effects on NSCLC tumorigenesis in vitro and in vivo. Therefore, P70S6K should be considered a new potential therapeutic target, and PF-470867 may be used as targeted drug for cancer treatment.
authors.affiliation: Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Zhi-Xin
authors.initials: ZX
authors.lastname: Qiu
authors.affiliation: Department of Respiratory Medicine, Tianjin First Central Hospital, Tianjin, 300192, China.
authors.forename: Rong-Fei
authors.initials: RF
authors.lastname: Sun
authors.affiliation: Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Mo
authors.affiliation: Department of Respiratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, China.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Li
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007093:Imidazoles; C552719:PF-4708671; D010879:Piperazines; D038762:Ribosomal Protein S6 Kinases, 70-kDa