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Tumor Biology

, Volume 37, Issue 7, pp 9709–9719 | Cite as

Iron chelator-induced apoptosis via the ER stress pathway in gastric cancer cells

  • Jung Lim Kim
  • Dae-Hee Lee
  • Yoo Jin Na
  • Bo Ram Kim
  • Yoon A. Jeong
  • Sun Il Lee
  • Sanghee Kang
  • Sung Yup Joung
  • Suk-Young Lee
  • Sang Cheul Oh
  • Byung Wook Min
Original Article

Abstract

Many reports have shown the anticancer effects of iron deficient on cancer cells, but the effects of iron-chelators on gastric cancer have not been clearly elucidated. Recently, we reported that iron chelators induced an antiproliferative effect in human malignant lymphoma and myeloid leukemia cells. In the present study, we investigated the antitumor activity of these two iron-chelating agents, deferoxamine (DFO) and deferasirox (DFX), with gastric cancer cell lines, and their apoptosis-inducing effects as the potential mechanism. We found that iron chelators displayed significant antiproliferative activity in human gastric cancer cell lines, which may be attributed to their induction of G1 phase arrest and apoptosis. We also found that iron chelators induced reactive oxygen species (ROS) production, resulting in the activation of both c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER) stress apoptotic pathways in gastric cancer cells. Taken together, our data suggest that iron chelators induced apoptosis in gastric cancer, involving ROS formation ER stress and JNK activation.

Keywords

Iron chelator Gastric cancer ER stress JNK 

Abbreviations

Bax

Bcl-2-associated X protein

DAPI

4′,6-Diamidino-2-phenylindole

FBS

Fetal bovine serum

FITC

Fluorescein isothiocyanate

JNK

c-Jun NH2-terminal kinase

MAPK

Mitogen-activated protein kinase

PBS

Phosphate-buffered saline

PARP

Poly(ADP-ribose) polymerase

PI

Propidium iodide

SDS-PAGE

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

ROS

Reactive oxygen species

ER

Endoplasmic reticulum

MTT

3-(4,5-Dimethylthiazol-2-ly)-2,5-diphenyl tetrazolium bromide

DFO

Deferoxamine

DFX

Deferasirox

GRP78

Glucose-regulated protein 78

GRP94

Glucose-regulated protein 94

ATF4

Activating transcription factor 4

ATF6

Activating transcription factor 6

eIF2α

Eukaryotic translation initiation factor 2α

CHOP

C/EBP-homologous protein

Notes

Acknowledgments

This study was supported by the Hanmi Pharm. Co., Ltd. (Grant number: 11500841) and the Brain Korea (BK) 21 Plus Program.

Compliance with ethical standards

Conflicts of interest

None

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Jung Lim Kim
    • 2
  • Dae-Hee Lee
    • 1
    • 2
  • Yoo Jin Na
    • 1
  • Bo Ram Kim
    • 1
  • Yoon A. Jeong
    • 2
  • Sun Il Lee
    • 3
  • Sanghee Kang
    • 3
  • Sung Yup Joung
    • 3
  • Suk-Young Lee
    • 2
  • Sang Cheul Oh
    • 1
    • 2
  • Byung Wook Min
    • 3
  1. 1.Brain Korea 21 Program for Biomedicine ScienceKorea University College of Medicine, Korea UniversitySeoulRepublic of Korea
  2. 2.Division of Oncology/Hematology, Department of Internal MedicineKorea University College of MedicineSeoulRepublic of Korea
  3. 3.Department of SurgeryKorea University Guro Hospital, Korea University College of MedicineSeoulKorea

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