Ellipticine-induced apoptosis depends on Akt translocation and signaling in lung epithelial cancer cells

Kang Fang, Shih Ping Chen, Chia Wei Lin, Wan Chun Cheng, Hwei Tien Huang

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)227-234
Number of pages8
JournalLung Cancer
Volume63
Issue number2
DOIs
Publication statusPublished - 2009 Feb

Keywords

  • Akt
  • Apoptosis
  • Ellipticine
  • Human non-small-cell-lung-cancer cells

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

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