Cargando…

A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases

Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features i...

Descripción completa

Detalles Bibliográficos
Autores principales: Ch'ng, J-H, Kotturi, S R, Chong, A G-L, Lear, M J, Tan, K S-W
Formato: Texto
Lenguaje:English
Publicado: Nature Publishing Group 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032337/
https://www.ncbi.nlm.nih.gov/pubmed/21364634
http://dx.doi.org/10.1038/cddis.2010.2
_version_ 1782197451572117504
author Ch'ng, J-H
Kotturi, S R
Chong, A G-L
Lear, M J
Tan, K S-W
author_facet Ch'ng, J-H
Kotturi, S R
Chong, A G-L
Lear, M J
Tan, K S-W
author_sort Ch'ng, J-H
collection PubMed
description Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxy-tamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (μM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD.
format Text
id pubmed-3032337
institution National Center for Biotechnology Information
language English
publishDate 2010
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-30323372011-02-24 A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases Ch'ng, J-H Kotturi, S R Chong, A G-L Lear, M J Tan, K S-W Cell Death Dis Original Article Several recent discoveries of the hallmark features of programmed cell death (PCD) in Plasmodium falciparum have presented the possibility of revealing novel targets for antimalarial therapy. Using a combination of cell-based assays, flow cytometry and fluorescence microscopy, we detected features including mitochondrial dysregulation, activation of cysteine proteases and in situ DNA fragmentation in parasites induced with chloroquine (CQ) and staurosporine (ST). The use of the pan-caspase inhibitor, z-Val-Ala-Asp-fmk (zVAD), and the mitochondria outer membrane permeabilization (MOMP) inhibitor, 4-hydroxy-tamoxifen, enabled the characterization of a novel CQ-induced pathway linking cysteine protease activation to downstream mitochondrial dysregulation, amplified protease activity and DNA fragmentation. The PCD features were observed only at high (μM) concentrations of CQ. The use of a new synthetic coumarin-labeled chloroquine (CM-CQ) showed that these features may be associated with concentration-dependent differences in drug localization. By further using cysteine protease inhibitors z-Asp-Glu-Val-Asp-fmk (zDEVD), z-Phe-Ala-fmk (zFA), z-Phe-Phe-fmk (zFF), z-Leu-Leu-Leu-fmk (zLLL), E64d and CA-074, we were able to implicate clan CA cysteine proteases in CQ-mediated PCD. Finally, CQ induction of two CQ-resistant parasite strains, 7G8 and K1, reveals the existence of PCD features in these parasites, the extent of which was less than 3D7. The use of the chemoreversal agent verapamil implicates the parasite digestive vacuole in mediating CQ-induced PCD. Nature Publishing Group 2010-02 2010-02-18 /pmc/articles/PMC3032337/ /pubmed/21364634 http://dx.doi.org/10.1038/cddis.2010.2 Text en Copyright © 2010 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This article is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 license. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Ch'ng, J-H
Kotturi, S R
Chong, A G-L
Lear, M J
Tan, K S-W
A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases
title A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases
title_full A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases
title_fullStr A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases
title_full_unstemmed A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases
title_short A programmed cell death pathway in the malaria parasite Plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan CA cysteine proteases
title_sort programmed cell death pathway in the malaria parasite plasmodium falciparum has general features of mammalian apoptosis but is mediated by clan ca cysteine proteases
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032337/
https://www.ncbi.nlm.nih.gov/pubmed/21364634
http://dx.doi.org/10.1038/cddis.2010.2
work_keys_str_mv AT chngjh aprogrammedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT kotturisr aprogrammedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT chongagl aprogrammedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT learmj aprogrammedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT tanksw aprogrammedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT chngjh programmedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT kotturisr programmedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT chongagl programmedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT learmj programmedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases
AT tanksw programmedcelldeathpathwayinthemalariaparasiteplasmodiumfalciparumhasgeneralfeaturesofmammalianapoptosisbutismediatedbyclancacysteineproteases