The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, sTRAIL:FeSOD, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells
<p>Abstract</p> <p>Background</p> <p>Many cancer cells develop resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, necessitating combination with chemotherapy, and normal cells manifest side effects due to the combined treatm...
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doaj-5dc9e3c97ec64461af092096e3d11cef2020-11-25T00:38:51ZengBMCBMC Biology1741-70072011-03-01911810.1186/1741-7007-9-18The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, sTRAIL:FeSOD, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cellsLi JianyongQin YongTang HongyunGong Xingguo<p>Abstract</p> <p>Background</p> <p>Many cancer cells develop resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, necessitating combination with chemotherapy, and normal cells manifest side effects due to the combined treatment regimen of TRAIL and chemotherapeutic drugs. A novel cancer therapy utilizing TRAIL is thus urgently needed.</p> <p>Results</p> <p>In this study, we exploited TRAIL receptor-mediated endocytosis for the first time to produce a cell-permeable molecule, soluble forms of recombinant TRAIL:iron superoxide dismutase (sTRAIL:FeSOD), which possesses sTRAIL-induced apoptotic ability and FeSOD antioxidant activity. The FeSOD component was rapidly introduced into the cell by sTRAIL and intracellular superoxide radical (O<sub>2</sub><sup>-</sup>), which have been implicated as potential modulators of apoptosis in cancer cells, was eliminated, resulting in a highly reduced cellular environment. The decrease in cellular O<sub>2</sub><sup>-</sup>, which was accompanied by a brief accumulation of H<sub>2</sub>O<sub>2 </sub>and downregulation of phosphorylated Akt (p-Akt) and cellular FLICE-inhibitory protein, sensitized K562 leukemia cells and human promyelocytic leukemia (HL-60) cells to TRAIL-induced apoptosis. The low H<sub>2</sub>O<sub>2 </sub>levels protected human LO2 hepatocytes from sTRAIL:FeSOD-induced apoptosis despite downregulation of p-Akt. We also obtained evidence that the lack of response to sTRAIL:FeSOD in normal T cells occurred because sTRAIL:FeSOD shows much stronger shifts of redox state in erythroleukemia (K562) and HL-60 cells compared to that in normal T cells. K562 and HL-60 cells underwent sTRAIL:FeSOD-induced apoptosis without the dysfunction of mitochondria.</p> <p>Conclusions</p> <p>The fusion protein overcomes the inability of FeSOD to permeate the cell membrane, exhibits synergistic apoptotic effects on K562 and HL-60 cells and demonstrates minimal toxicity to normal T cells and the normal liver cell line LO2, indicating its potential value for the treatment of leukemia.</p> http://www.biomedcentral.com/1741-7007/9/18 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Li Jianyong Qin Yong Tang Hongyun Gong Xingguo |
spellingShingle |
Li Jianyong Qin Yong Tang Hongyun Gong Xingguo The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, sTRAIL:FeSOD, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells BMC Biology |
author_facet |
Li Jianyong Qin Yong Tang Hongyun Gong Xingguo |
author_sort |
Li Jianyong |
title |
The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, sTRAIL:FeSOD, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells |
title_short |
The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, sTRAIL:FeSOD, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells |
title_full |
The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, sTRAIL:FeSOD, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells |
title_fullStr |
The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, sTRAIL:FeSOD, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells |
title_full_unstemmed |
The scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, sTRAIL:FeSOD, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells |
title_sort |
scavenging of superoxide radicals promotes apoptosis induced by a novel cell-permeable fusion protein, strail:fesod, in tumor necrosis factor-related apoptosis-inducing ligand-resistant leukemia cells |
publisher |
BMC |
series |
BMC Biology |
issn |
1741-7007 |
publishDate |
2011-03-01 |
description |
<p>Abstract</p> <p>Background</p> <p>Many cancer cells develop resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, necessitating combination with chemotherapy, and normal cells manifest side effects due to the combined treatment regimen of TRAIL and chemotherapeutic drugs. A novel cancer therapy utilizing TRAIL is thus urgently needed.</p> <p>Results</p> <p>In this study, we exploited TRAIL receptor-mediated endocytosis for the first time to produce a cell-permeable molecule, soluble forms of recombinant TRAIL:iron superoxide dismutase (sTRAIL:FeSOD), which possesses sTRAIL-induced apoptotic ability and FeSOD antioxidant activity. The FeSOD component was rapidly introduced into the cell by sTRAIL and intracellular superoxide radical (O<sub>2</sub><sup>-</sup>), which have been implicated as potential modulators of apoptosis in cancer cells, was eliminated, resulting in a highly reduced cellular environment. The decrease in cellular O<sub>2</sub><sup>-</sup>, which was accompanied by a brief accumulation of H<sub>2</sub>O<sub>2 </sub>and downregulation of phosphorylated Akt (p-Akt) and cellular FLICE-inhibitory protein, sensitized K562 leukemia cells and human promyelocytic leukemia (HL-60) cells to TRAIL-induced apoptosis. The low H<sub>2</sub>O<sub>2 </sub>levels protected human LO2 hepatocytes from sTRAIL:FeSOD-induced apoptosis despite downregulation of p-Akt. We also obtained evidence that the lack of response to sTRAIL:FeSOD in normal T cells occurred because sTRAIL:FeSOD shows much stronger shifts of redox state in erythroleukemia (K562) and HL-60 cells compared to that in normal T cells. K562 and HL-60 cells underwent sTRAIL:FeSOD-induced apoptosis without the dysfunction of mitochondria.</p> <p>Conclusions</p> <p>The fusion protein overcomes the inability of FeSOD to permeate the cell membrane, exhibits synergistic apoptotic effects on K562 and HL-60 cells and demonstrates minimal toxicity to normal T cells and the normal liver cell line LO2, indicating its potential value for the treatment of leukemia.</p> |
url |
http://www.biomedcentral.com/1741-7007/9/18 |
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