Please use this identifier to cite or link to this item: https://doi.org/10.1371/journal.pone.0058578
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dc.titleA Unifying Mechanism for Cancer Cell Death through Ion Channel Activation by HAMLET
dc.contributor.authorStorm P.
dc.contributor.authorKjaer Klausen T.
dc.contributor.authorTrulsson M.
dc.contributor.authorHo CS J.
dc.contributor.authorDosnon M.
dc.contributor.authorWestergren T.
dc.contributor.authorChao Y.
dc.contributor.authorRydström A.
dc.contributor.authorYang H.
dc.contributor.authorPedersen S.F.
dc.contributor.authorSvanborg C.
dc.date.accessioned2019-11-04T06:28:48Z
dc.date.available2019-11-04T06:28:48Z
dc.date.issued2013
dc.identifier.citationStorm P., Kjaer Klausen T., Trulsson M., Ho CS J., Dosnon M., Westergren T., Chao Y., Rydström A., Yang H., Pedersen S.F., Svanborg C. (2013). A Unifying Mechanism for Cancer Cell Death through Ion Channel Activation by HAMLET. PLoS ONE 8 (3) : e58578. ScholarBank@NUS Repository. https://doi.org/10.1371/journal.pone.0058578
dc.identifier.issn19326203
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/161337
dc.description.abstractIon 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. © 2013 Storm et al.
dc.sourceUnpaywall 20191101
dc.subjectantineoplastic agent
dc.subjectcalcium ion
dc.subjecthuman alpha lactalbumin made lethal to tumor cell
dc.subjectmitogen activated protein kinase p38
dc.subjectpotassium ion
dc.subjectsodium ion
dc.subjectunclassified drug
dc.subjectantineoplastic activity
dc.subjectapoptosis
dc.subjectarticle
dc.subjectcell structure
dc.subjectcell viability
dc.subjectcontrolled study
dc.subjectenzyme activation
dc.subjectenzyme inhibition
dc.subjectenzyme phosphorylation
dc.subjecthuman
dc.subjecthuman cell
dc.subjectimmunostimulation
dc.subjection transport
dc.subjectnucleotide sequence
dc.subjectsignal transduction
dc.subjecttumor cell destruction
dc.subjectBiological Transport
dc.subjectCalcium
dc.subjectCell Death
dc.subjectCell Line, Tumor
dc.subjectCluster Analysis
dc.subjectGene Expression Profiling
dc.subjectHumans
dc.subjectImmunity, Innate
dc.subjectIntracellular Space
dc.subjectIon Channels
dc.subjectLactalbumin
dc.subjectOleic Acids
dc.subjectp38 Mitogen-Activated Protein Kinases
dc.subjectPhosphorylation
dc.subjectPotassium
dc.subjectSignal Transduction
dc.subjectSodium
dc.typeArticle
dc.contributor.departmentDUKE-NUS MEDICAL SCHOOL
dc.contributor.departmentCANCER SCIENCE INSTITUTE OF SINGAPORE
dc.description.doi10.1371/journal.pone.0058578
dc.description.sourcetitlePLoS ONE
dc.description.volume8
dc.description.issue3
dc.description.pagee58578
dc.published.statePublished
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