Abstract | BACKGROUND: 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. RESULTS: 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 (O2-), 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 O2-, which was accompanied by a brief accumulation of H2O2 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 H2O2 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. CONCLUSIONS: 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.
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Authors | Hongyun Tang, Yong Qin, Jianyong Li, Xingguo Gong |
Journal | BMC biology
(BMC Biol)
Vol. 9
Pg. 18
(Mar 19 2011)
ISSN: 1741-7007 [Electronic] England |
PMID | 21418589
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- Recombinant Fusion Proteins
- TNF-Related Apoptosis-Inducing Ligand
- TNFRSF10A protein, human
- Tumor Necrosis Factor-alpha
- Superoxides
- Hydrogen Peroxide
- Superoxide Dismutase
- Proto-Oncogene Proteins c-akt
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Topics |
- Apoptosis
(drug effects)
- HL-60 Cells
- Humans
- Hydrogen Peroxide
(metabolism)
- K562 Cells
- Proto-Oncogene Proteins c-akt
(metabolism)
- Receptors, TNF-Related Apoptosis-Inducing Ligand
(metabolism)
- Recombinant Fusion Proteins
(pharmacology)
- Superoxide Dismutase
(pharmacology)
- Superoxides
(metabolism)
- TNF-Related Apoptosis-Inducing Ligand
(pharmacology)
- Tumor Necrosis Factor-alpha
(pharmacology)
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