Molecular and Cellular Biochemistry

, Volume 318, Issue 1, pp 23–31

Adaptive response to GSH depletion and resistance to l-buthionine-(S,R)-sulfoximine: involvement of Nrf2 activation

  • Hyang-Rim Lee
  • Jeong-Min Cho
  • Dong-ha Shin
  • Chul Soon Yong
  • Han-Gon Choi
  • Nobunao Wakabayashi
  • Mi-Kyoung Kwak
Article

DOI: 10.1007/s11010-008-9853-y

Cite this article as:
Lee, H., Cho, J., Shin, D. et al. Mol Cell Biochem (2008) 318: 23. doi:10.1007/s11010-008-9853-y

Abstract

Pharmacological depletion of l-γ-glutamyl-l-cysteinyl-glycine (GSH) has been implicated in the sensitization of cancer cells to alkylating agents and apoptosis. However, some types of cells do not induce apoptotic response following chemical depletion of GSH. In the present study, we report that murine embryonic fibroblasts (MEFs) can survive in the presence of GSH inhibitor l-buthionine-(S,R)-sulfoximine (BSO), even though most intracellular GSH was depleted. As a cellular adaptive mechanism, BSO treatment effectively activated the NF-E2-related factor 2 (Nrf2) pathway, which led to up-regulation of antioxidant enzymes in these cells through the extracellular signal-regulated kinase cascade. While nrf2-deficient MEFs lost the inducibility of antioxidant genes, which resulted in higher levels of reactive oxygen species accumulation, caspase-3 activation, and cell death than wild-type cells. Finally, nrf2-deficient cells can be more sensitized to doxorubicin-induced cell death by BSO pre-incubation, while wild-type cells were not. In addition, BSO-mediated cell death was facilitated by administering Nrf2 siRNA to chemoresistant human ovarian cancer cells. These results indicate that Nrf2 is the primary factor inducing the cell survival system under GSH depletion and that the effect of BSO as a chemosensitizer might be enhanced by inhibition of Nrf2.

Keywords

GSHBSOOxidative stressNrf2Chemosensitizer

Abbreviations

GSH

Glutathione

GCLC

Catalytic subunit of γ-glutamylcysteine ligase

GCLM

Modulatory subunit of γ-glutamylcysteine ligase

Nqo1

NAD(P)H: quinone oxidoreductase 1

ARE

Antioxidant response element

BSO

l-Buthionine-(S,R)-sulfoximine

ROS

Reactive oxygen speices

MAPK

Mitogen-activated protein kinase

ERK

Extracellular signal-regulated kinase

JNK

c-Jun N-terminal kinase

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • Hyang-Rim Lee
    • 1
  • Jeong-Min Cho
    • 1
  • Dong-ha Shin
    • 1
  • Chul Soon Yong
    • 1
  • Han-Gon Choi
    • 1
  • Nobunao Wakabayashi
    • 2
  • Mi-Kyoung Kwak
    • 1
  1. 1.College of PharmacyYeungnam UniversityGyeongsan-siSouth Korea
  2. 2.Johns Hopkins UniversityBaltimoreUSA