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RNA-dependent protein kinase is essential for 2-methoxyestradiol-induced autophagy in osteosarcoma cells.
- Source :
-
PloS one [PLoS One] 2013; Vol. 8 (3), pp. e59406. Date of Electronic Publication: 2013 Mar 19. - Publication Year :
- 2013
-
Abstract
- Osteosarcoma is the most common primary malignant bone tumor in children and young adults. Surgical resection and adjunctive chemotherapy are the only widely available options of treatment for this disease. Anti-tumor compound 2-Methoxyestradiol (2-ME) triggers cell death through the induction of apoptosis in osteosarcoma cells, but not in normal osteoblasts. In this report, we have investigated whether autophagy plays a role in 2-ME actions on osteosarcoma cells. Transmission electron microscopy imaging shows that 2-ME treatment leads to the accumulation of autophagosomes in human osteosarcoma cells. 2-ME induces the conversion of the microtubule-associated protein LC3-I to LC3-II, a biochemical marker of autophagy that is correlated with the formation of autophagosomes. Conversion to LC3-II is accompanied by protein degradation in 2-ME-treated cells. 2-ME does not induce autophagosome formation in normal primary human osteoblasts. In addition, 2-ME-dependent autophagosome formation in osteosarcoma cells requires ATG7 expression. Furthermore, 2-ME does not induce accumulation of autophagosomes in osteosarcoma cells that express dominant negative mutant RNA-dependent protein kinase (PKR) and are resistant to anti-proliferative and anti-tumor effects of 2-ME. Taken together, our study shows that 2-ME treatment induces PKR-dependent autophagy in osteosarcoma cells, and that autophagy could play an important role in 2-ME-mediated anti-tumor actions and in the control of osteosarcoma.
- Subjects :
- 2-Methoxyestradiol
Analysis of Variance
Autophagy-Related Protein 7
Blotting, Western
Cell Line, Tumor
Estradiol metabolism
Estradiol pharmacology
Humans
Immunoprecipitation
Microscopy, Electron, Transmission
Microtubule-Associated Proteins genetics
Microtubule-Associated Proteins metabolism
Osteosarcoma ultrastructure
RNA, Small Interfering genetics
Ubiquitin-Activating Enzymes metabolism
Autophagy drug effects
Estradiol analogs & derivatives
Osteosarcoma physiopathology
eIF-2 Kinase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 8
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 23527187
- Full Text :
- https://doi.org/10.1371/journal.pone.0059406