A Unifying Mechanism for Cancer Cell Death through Ion Channel Activation by HAMLET.

Summary, in English

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.

• Author: Petter Storm; Thomas Kjaer Klausen; Maria Trulsson; James Ho Cs; Marion Dosnon; Tomas Westergren; Yinxia Chao; Anna Rydström; Henry Yang; Stine Falsig Pedersen; Catharina Svanborg
• Department/s: Division of Microbiology, Immunology and Glycobiology - MIG; Translational Muscle Research
• Publishing year: 2013
• Language: English
• Publication/Series: PLoS ONE
• Volume: 8
• Issue: 3
• Full text: - 3 MB; Download statistics
• Links: http://www.ncbi.nlm.nih.gov/pubmed/23505537?dopt=Abstract; http://dx.doi.org/10.1371/journal.pone.0058578
• Document type: Journal article
• Publisher: Public Library of Science (PLoS)
• Topic: Immunology in the medical area; Microbiology in the medical area; Endocrinology and Diabetes
• Status: Published
• Research group: Genomics, Diabetes and Endocrinology
• ISBN/ISSN/Other: ISSN: 1932-6203