Molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.

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...

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Autores principales: Neil Hoa, Michael P Myers, Thomas G Douglass, Jian Gang Zhang, Christina Delgado, Lara Driggers, Linda L Callahan, Gerald VanDeusen, Jimmy T H Pham, Nirav Bhakta, Lisheng Ge, Martin R Jadus
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Publicado: Public Library of Science (PLoS) 2009
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spelling oai:doaj.org-article:bca2e9701c7f469bb6ddbe409ccc802f2021-11-25T06:17:03ZMolecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.1932-620310.1371/journal.pone.0004631https://doaj.org/article/bca2e9701c7f469bb6ddbe409ccc802f2009-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19247476/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Paraptosis 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.Neil HoaMichael P MyersThomas G DouglassJian Gang ZhangChristina DelgadoLara DriggersLinda L CallahanGerald VanDeusenJimmy T H PhamNirav BhaktaLisheng GeMartin R JadusPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 4, Iss 2, p e4631 (2009)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Neil Hoa
Michael P Myers
Thomas G Douglass
Jian Gang Zhang
Christina Delgado
Lara Driggers
Linda L Callahan
Gerald VanDeusen
Jimmy T H Pham
Nirav Bhakta
Lisheng Ge
Martin R Jadus
Molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.
description 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.
format article
author Neil Hoa
Michael P Myers
Thomas G Douglass
Jian Gang Zhang
Christina Delgado
Lara Driggers
Linda L Callahan
Gerald VanDeusen
Jimmy T H Pham
Nirav Bhakta
Lisheng Ge
Martin R Jadus
author_facet Neil Hoa
Michael P Myers
Thomas G Douglass
Jian Gang Zhang
Christina Delgado
Lara Driggers
Linda L Callahan
Gerald VanDeusen
Jimmy T H Pham
Nirav Bhakta
Lisheng Ge
Martin R Jadus
author_sort Neil Hoa
title Molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.
title_short Molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.
title_full Molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.
title_fullStr Molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.
title_full_unstemmed Molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.
title_sort molecular mechanisms of paraptosis induction: implications for a non-genetically modified tumor vaccine.
publisher Public Library of Science (PLoS)
publishDate 2009
url https://doaj.org/article/bca2e9701c7f469bb6ddbe409ccc802f
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