Tumor Biology

, Volume 37, Issue 7, pp 9615–9624 | Cite as

Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway

  • Kyoung Ah Kang
  • Mei Jing Piao
  • Susara Ruwan Kumara Madduma Hewage
  • Yea Seong Ryu
  • Min Chang Oh
  • Taeg Kyu Kwon
  • Sungwook Chae
  • Jin Won Hyun
Original Article


Fisetin (3,3′,4′,7-tetrahydroxyflavone), a dietary flavonoid compound, is currently being investigated for its anticancer effect in various cancer models, including lung cancer. Recent studies show that fisetin induces cell growth inhibition and apoptosis in the human non-small cell lung cancer line NCI-H460. In this study, we investigated whether fisetin can induce endoplasmic reticulum (ER) stress-mediated apoptosis in NCI-H460 cells. Fisetin induced mitochondrial reactive oxygen species (ROS) and characteristic signs of ER stress: ER staining; mitochondrial Ca2+ overload; expression of ER stress-related proteins; glucose-regulated protein (GRP)-78, phosphorylation of protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylation of eukaryotic initiation factor-2 α subunit; cleavage of activating transcription factor-6; phosphorylation of inositol-requiring kinase-1 and splicing of X-box transcription factor-1; induction of C/EBP homologous protein and cleaved caspase-12. siRNA-mediated knockdown of CHOP and ATF-6 attenuated fisetin-induced apoptotic cell death. In addition, fisetin induced phosphorylation of ERK, JNK, and p38 MAPK. Moreover, silencing of the MAPK signaling pathway prevented apoptotic cell death. In summary, our results indicate that, in NCI-H460 cells, fisetin induces apoptosis and ER stress that is mediated by induction of the MAPK signaling pathway.


Fisetin Human non-small cell lung cancer Apoptosis Reactive oxygen species ER stress MAPK signaling pathway 



This work was supported by Grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2013R1A1A2010042).

Compliance with ethical standards

Conflicts of interest



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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Kyoung Ah Kang
    • 1
  • Mei Jing Piao
    • 1
  • Susara Ruwan Kumara Madduma Hewage
    • 1
  • Yea Seong Ryu
    • 1
  • Min Chang Oh
    • 1
  • Taeg Kyu Kwon
    • 2
  • Sungwook Chae
    • 3
  • Jin Won Hyun
    • 1
  1. 1.Department of Biochemistry, School of MedicineJeju National UniversityJejuRepublic of Korea
  2. 2.Department of Immunology, School of MedicineKeimyung UniversityDaeguRepublic of Korea
  3. 3.Aging Research CenterKorea Institute of Oriental MedicineDaejeonRepublic of Korea

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