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Endoplasmic reticulum stress exacerbates ischemia‐reperfusion‐induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells
Author(s) -
Yung Hongwa,
Korolchuk Svitlana,
Tolkovsky Aviva M.,
CharnockJones D. Stephen,
Burton Graham J.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6054com
Subject(s) - protein kinase b , unfolded protein response , endoplasmic reticulum , pi3k/akt/mtor pathway , microbiology and biotechnology , apoptosis , thapsigargin , oxidative stress , ly294002 , chemistry , signal transduction , cancer research , biology , endocrinology , biochemistry
Oxidative stress is central to ischemia‐reperfusion injury. The role of the endoplasmic reticulum (ER) in this process is uncertain. In ER signaling, PERK‐Nrf2 and Ire‐CHOP are two pathways that determine cell fate under stress. PERK‐Nrf2 up‐regulates antioxidant enzyme expression whereas Ire‐CHOP promotes apoptosis. We have identified a novel pathway in ER stress‐induced apoptosis after ischemia‐reperfusion in vitro involving translational suppression of the survival kinase PKB/Akt (Akt), and elucidated an alternative protective role of antioxidants in the regulation of Akt activity. Using human choriocarcinoma JEG‐3 cells, we found that sustained activation of ER stress by tunicamycin or thapsigargin exacerbated apoptosis in oxygen‐glucose‐deprived cells during reoxygenation. This was mediated via a reduction in phosphorylated Akt secondary to down‐regulation of protein translation rather than suppression of phosphorylation. Transient overexpression of wild‐type Akt, but not kinase‐dead Akt, in JEG‐3 cells diminished tunicamycin‐OGD reoxy‐genation‐induced apoptosis. The antioxidants Trolox and Edaravone reduced apoptosis, but the protective effect of Trolox was abrogated by the PI3K inhibitor, LY294002. We speculate that sustained ER stress may contribute to the placental dysfunction seen in human pregnancy complications.—Yung, H‐w., Korolchuk, S., Tolkovsky, A. M., Charnock‐Jones, D. S., Burton, G. J. Endoplasmic reticulum stress exacerbates ischemiareperfusion‐induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells. FASEB J. 21, 872–884 (2007)