A unifying mechanism for cancer cell death through ion channel activation by HAMLET.

Ion channels and ion fluxes control many aspects of tissue homeostasis. During oncogenic transformation, critical ion channel functions may be perturbed but conserved tumor specific ion fluxes remain to be defined. Here we used the tumoricidal protein-lipid complex HAMLET as a probe to identify ion...

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Autores principales:	Petter Storm, Thomas Kjaer Klausen, Maria Trulsson, James Ho C S, Marion Dosnon, Tomas Westergren, Yinxia Chao, Anna Rydström, Henry Yang, Stine Falsig Pedersen, Catharina Svanborg
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/69fb7928210a4b369b293ff6c9371286
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spelling	oai:doaj.org-article:69fb7928210a4b369b293ff6c93712862021-11-18T07:54:20ZA unifying mechanism for cancer cell death through ion channel activation by HAMLET.1932-620310.1371/journal.pone.0058578https://doaj.org/article/69fb7928210a4b369b293ff6c93712862013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23505537/?tool=EBIhttps://doaj.org/toc/1932-6203Ion channels and ion fluxes control many aspects of tissue homeostasis. During oncogenic transformation, critical ion channel functions may be perturbed but conserved tumor specific ion fluxes remain to be defined. Here we used the tumoricidal protein-lipid complex HAMLET as a probe to identify ion fluxes involved in tumor cell death. We show that HAMLET activates a non-selective cation current, which reached a magnitude of 2.74±0.88 nA within 1.43±0.13 min from HAMLET application. Rapid ion fluxes were essential for HAMLET-induced carcinoma cell death as inhibitors (amiloride, BaCl2), preventing the changes in free cellular Na(+) and K(+) concentrations also prevented essential steps accompanying carcinoma cell death, including changes in morphology, uptake, global transcription, and MAP kinase activation. Through global transcriptional analysis and phosphorylation arrays, a strong ion flux dependent p38 MAPK response was detected and inhibition of p38 signaling delayed HAMLET-induced death. Healthy, differentiated cells were resistant to HAMLET challenge, which was accompanied by innate immunity rather than p38-activation. The results suggest, for the first time, a unifying mechanism for the initiation of HAMLET's broad and rapid lethal effect on tumor cells. These findings are particularly significant in view of HAMLET's documented therapeutic efficacy in human studies and animal models. The results also suggest that HAMLET offers a two-tiered therapeutic approach, killing cancer cells while stimulating an innate immune response in surrounding healthy tissues.Petter StormThomas Kjaer KlausenMaria TrulssonJames Ho C SMarion DosnonTomas WestergrenYinxia ChaoAnna RydströmHenry YangStine Falsig PedersenCatharina SvanborgPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 3, p e58578 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Petter Storm Thomas Kjaer Klausen Maria Trulsson James Ho C S Marion Dosnon Tomas Westergren Yinxia Chao Anna Rydström Henry Yang Stine Falsig Pedersen Catharina Svanborg A unifying mechanism for cancer cell death through ion channel activation by HAMLET.
description	Ion channels and ion fluxes control many aspects of tissue homeostasis. During oncogenic transformation, critical ion channel functions may be perturbed but conserved tumor specific ion fluxes remain to be defined. Here we used the tumoricidal protein-lipid complex HAMLET as a probe to identify ion fluxes involved in tumor cell death. We show that HAMLET activates a non-selective cation current, which reached a magnitude of 2.74±0.88 nA within 1.43±0.13 min from HAMLET application. Rapid ion fluxes were essential for HAMLET-induced carcinoma cell death as inhibitors (amiloride, BaCl2), preventing the changes in free cellular Na(+) and K(+) concentrations also prevented essential steps accompanying carcinoma cell death, including changes in morphology, uptake, global transcription, and MAP kinase activation. Through global transcriptional analysis and phosphorylation arrays, a strong ion flux dependent p38 MAPK response was detected and inhibition of p38 signaling delayed HAMLET-induced death. Healthy, differentiated cells were resistant to HAMLET challenge, which was accompanied by innate immunity rather than p38-activation. The results suggest, for the first time, a unifying mechanism for the initiation of HAMLET's broad and rapid lethal effect on tumor cells. These findings are particularly significant in view of HAMLET's documented therapeutic efficacy in human studies and animal models. The results also suggest that HAMLET offers a two-tiered therapeutic approach, killing cancer cells while stimulating an innate immune response in surrounding healthy tissues.
format	article
author	Petter Storm Thomas Kjaer Klausen Maria Trulsson James Ho C S Marion Dosnon Tomas Westergren Yinxia Chao Anna Rydström Henry Yang Stine Falsig Pedersen Catharina Svanborg
author_facet	Petter Storm Thomas Kjaer Klausen Maria Trulsson James Ho C S Marion Dosnon Tomas Westergren Yinxia Chao Anna Rydström Henry Yang Stine Falsig Pedersen Catharina Svanborg
author_sort	Petter Storm
title	A unifying mechanism for cancer cell death through ion channel activation by HAMLET.
title_short	A unifying mechanism for cancer cell death through ion channel activation by HAMLET.
title_full	A unifying mechanism for cancer cell death through ion channel activation by HAMLET.
title_fullStr	A unifying mechanism for cancer cell death through ion channel activation by HAMLET.
title_full_unstemmed	A unifying mechanism for cancer cell death through ion channel activation by HAMLET.
title_sort	unifying mechanism for cancer cell death through ion channel activation by hamlet.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/69fb7928210a4b369b293ff6c9371286
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A unifying mechanism for cancer cell death through ion channel activation by HAMLET.

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