Molecular Mechanisms of Paraptosis Induction: Implications for a Non-Genetically Modified Tumor Vaccine
| Autor: | Christina Delgado, Neil Hoa, Lisheng Ge, Martin R. Jadus, Jimmy T. H. Pham, Thomas Douglass, Lara Driggers, Nirav Bhakta, Jian Gang Zhang, Gerald Vandeusen, Michael P. Myers, Linda L. Callahan |
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| Rok vydání: | 2009 |
| Předmět: |
Macrophage colony-stimulating factor
BK channel Programmed cell death Science Immunology Apoptosis Endoplasmic Reticulum Cancer Vaccines Paraptosis Adenosine Triphosphate Immune system Cell Line Tumor Medicine and Health Sciences Animals Macrophage Large-Conductance Calcium-Activated Potassium Channels Oncology/Neuro-Oncology Microscopy Confocal Multidisciplinary biology Macrophages Cell Membrane Cell Biology/Cellular Death and Stress Responses Mitochondria Rats Cell biology Microscopy Electron Phloretin Cell culture Gene Knockdown Techniques biology.protein Medicine Mitochondrial Swelling Peptides Reactive Oxygen Species Research Article |
| Zdroj: | PLoS ONE Hoa, Neil; Myers, Michael P.; Douglass, Thomas G.; Zhang, Jian Gang; Delgado, Christina; Driggers, Lara; et al.(2009). Molecular Mechanisms of Paraptosis Induction: Implications for a Non-Genetically Modified Tumor Vaccine. PLoS One, 4(2), e4631. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/9rz4r3nb PLoS ONE, Vol 4, Iss 2, p e4631 (2009) |
| ISSN: | 1932-6203 |
| Popis: | Paraptosis is the programmed cell death pathway that leads to cellular necrosis. Previously, rodent and human monocytes/macrophages killed glioma cells bearing the membrane macrophage colony stimulating factor (mM-CSF) through paraptosis, but the molecular mechanism of this killing process was never identified. We have demonstrated that paraptosis of rat T9 glioma cells can be initiated through a large potassium channel (BK)-dependent process initiated by reactive oxygen species. Macrophage mediated cytotoxicity upon the mM-CSF expressing T9-C2 cells was not prevented by the addition of the caspase inhibitor, zVAD-fmk. By a combination of fluorescent confocal and electron microscopy, flow cytometry, electrophysiology, pharmacology, and genetic knock-down approaches, we demonstrated that these ion channels control cellular swelling and vacuolization of rat T9 glioma cells. Cell lysis is preceded by a depletion of intracellular ATP. Six-hour exposure to BK channel activation caused T9 cells to over express heat shock proteins (Hsp 60, 70, 90 and gp96). This same treatment forced HMGB1 translocation from the nuclear region to the periphery. These last molecules are "danger signals" that can stimulate immune responses. Similar inductions of mitochondrial swelling and increased Hsp70 and 90 expressions by BK channel activation were observed with the non-immunogenic F98 glioma cells. Rats injected with T9 cells which were killed by prolonged BK channel activation developed immunity against the T9 cells, while the injection of x-irradiated apoptotic T9 cells failed to produce the vaccinating effect. These results are the first to show that glioma cellular death induced by prolonged BK channel activation improves tumor immunogenicity; this treatment reproduces the vaccinating effects of mM-CSF transduced cells. Elucidation of strategies as described in this study may prove quite valuable in the development of clinical immunotherapy against cancer. |
| Databáze: | OpenAIRE |
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