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- Title
Impairment of Na<sup>+</sup>,K<sup>+</sup>-ATPase in CD95(APO-1)-induced human T-cell leukemia cell apoptosis mediated by glutathione depletion and generation of hydrogen peroxide.
- Authors
Yin, W.; Cheng, W.; Shen, W.; Shu, L.; Zhao, J.; Zhang, J.; Hua, Z.-C.
- Abstract
Human T-cell leukemia is a malignant disease that needs various regimens of cytotoxic chemotherapy to overcome drug resistance. Recently, Na+,K+-ATPase has emerged as a potential target for cancer therapy. However, its exact signaling pathway in human T-cell leukemia cell death has not been well defined. In the current study, we found CD95(APO-1) was able to trigger the internalization of plasma membrane Na+,K+-ATPase in Jurkat cells or primary T cells as a mechanism to suppress its activity. This internalization was closely relevant to intracellular glutathione (GSH) depletion in Jurkat cells downstream of Fas-associated death domain protein (FADD) and caspase 8. GSH depletion in Fas L-treated Jurkat cells induced the generation of hydrogen peroxide (H2O2), which subsequently increased the serine phosphorylation of Na+,K+-ATPase α1 subunit. Exogenous H2O2 even mimicked the effect of Fas L to upregulate the serine phosphorylation of Na+,K+-ATPase α1 subunit and suppress Na+,K+-ATPase activity. Overall, our results indicate that CD95(APO-1) induces the FADD- and caspase 8-dependent internalization of Na+,K+-ATPase through intracellular GSH loss, and the subsequent generation of H2O2-mediated serine phosphorylation of Na+,K+-ATPase α1 subunit. Taken together, this study presents a novel regulatory mechanism of Na+,K+-ATPase in CD95(APO-1)-mediated human T-leukemia cell apoptosis.Leukemia (2007) 21, 1669–1678; doi:10.1038/sj.leu.2404791; published online 7 June 2007
- Subjects
ADULT T-cell leukemia; HTLV; DRUG resistance; ADENOSINE triphosphatase; CANCER treatment; CELL death; CHEMICAL reactions
- Publication
Leukemia (08876924), 2007, Vol 21, Issue 8, p1669
- ISSN
0887-6924
- Publication type
Article
- DOI
10.1038/sj.leu.2404791