Artocarpin, an isoprenyl flavonoid, induces p53-dependent or independent apoptosis via ROS-mediated MAPKs and Akt activation in non-small cell lung cancer cells

Ming Horng Tsai, Ju Fang Liu, Yao Chang Chiang, Stephen Chu Sung Hu, Lee Fen Hsu, Yu Ching Lin, Zih Chan Lin, Hui Chun Lee, Mei Chuan Chen, Chieh Liang Huang, Chiang Wen Lee

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Artocarpin has been shown to exhibit cytotoxic effects on different cancer cells, including non-small cell lung carcinoma (NSCLC, A549). However, the underlying mechanisms remain unclear. Here, we explore both p53-dependent and independent apoptosis pathways in artocarpin-treated NSCLC cells. Our results showed that artocarpin rapidly induced activation of cellular protein kinases including Erk1/2, p38 and AktS473. Inhibition of these protein kinases prevented artocarpin-induced cell death. Moreover, artocarpin-induced phosphorylation of these protein kinases and apoptosis were mediated by induction of reactive oxygen species (ROS), as pretreatment with NAC (a ROS scavenger) and Apocynin (a Nox-2 inhibitor) blocked these events. Similarly, transient transfection of p47Phox or p91Phox siRNA attenuated artocarpininduced NADPH oxidase activity and cell death. In addition, p53 dependent apoptotic proteins including PUMA, cytochrome c, Apaf-1 and caspase 3 were activated by artocarpin, and these effects can be abolished by antioxidants, MAPK inhibitors (U0126 and SB202190), but not by PI3K inhibitor (LY294002). Furthermore, we found that artocarpin-induced Akt phosphorylation led to increased NF-κB activity, which may act as an upstream regulator in the c-Myc and Noxa pathway. Therefore, we propose that enhancement of both ERK/ p38/ p53-dependent or independent AktS473/NF-κB/c-Myc/Noxa cascade by Nox-derived ROS generation plays an important role in artocarpin-induced apoptosis in NSCLC cells.

Original languageEnglish
Pages (from-to)28342-28358
Number of pages17
JournalOncotarget
Volume8
Issue number17
DOIs
Publication statusPublished - 2017

Keywords

  • Apoptosis
  • Artocarpin
  • Lung cancer
  • P53
  • Pro-oxidation

ASJC Scopus subject areas

  • Oncology

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