title: Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells.
abstract: Ellipticine and its analogues were reported as topoisomerase II inhibitors and promising antitumor agents. In this work, we showed that the growth of human non-small-cell-lung-cancer (NSCLC) epithelial cells A549 can be inhibited by ellipticine. The inhibitory effect was reverted by PI3K inhibitors. The sub-G(1) phase cells after ellipticine treatment appeared at the expense of those that accumulated first at S- and G(2)/M phases during the early stage of treatment. We showed that the progression leading to cell death was impaired by wortmannin, which reverted apoptosis by retaining cells at S- and G(2)/M transition states. The characteristic apoptosis marker p53 activation after treatment appeared first followed by poly(ADP-ribose)polymerase (PARP) fragmentation. They disappeared upon co-treatment with wortmannin and the apoptotic phenotype reversed. Furthermore, ellipticine regulated endogenous survival signaling by up-regulating phosphorylated Akt that returned to its basal level later. Furthermore, ellipticine induced nucleus translocalization of p53 and Akt and recruitment of autophagosomes. The autophagic-related cell death was interfered by wortmannin and the suppressed growth reverted. The Akt-related cell death also occurred in p53-deficient cells with stable expression of exogenous p53. The work showed that ellipticine-induced cytotoxicity in NSCLC cells was achieved through autophagy and apoptotic death as a result of Akt-modulation. Being a topoisomerase II inhibitor, ellipticine proved a regulator in autophagy-related cell death through corporation of p53 and Akt.
authors.affiliation: Department of Life Science, National Taiwan Normal University, Taipei, Taiwan. biofv033@scc.ntnu.edu.tw
authors.forename: Kang
authors.initials: K
authors.lastname: Fang
authors.forename: Shih-Ping
authors.initials: SP
authors.lastname: Chen
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Lin
authors.forename: Wan-Chun
authors.initials: WC
authors.lastname: Cheng
authors.forename: Hwei-Tien
authors.initials: HT
authors.lastname: Huang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000730:Androstadienes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004611:Ellipticines / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000970:Antineoplastic Agents; D004611:Ellipticines; D016159:Tumor Suppressor Protein p53; C034192:ellipticine; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin