title: Targeting TRPM2 Channels Impairs Radiation-Induced Cell Cycle Arrest and Fosters Cell Death of T Cell Leukemia Cells in a Bcl-2-Dependent Manner.
abstract: Messenger RNA data of lymphohematopoietic cancer lines suggest a correlation between expression of the cation channel TRPM2 and the antiapoptotic protein Bcl-2. The latter is overexpressed in various tumor entities and mediates therapy resistance. Here, we analyzed the crosstalk between Bcl-2 and TRPM2 channels in T cell leukemia cells during oxidative stress as conferred by ionizing radiation (IR). To this end, the effects of TRPM2 inhibition or knock-down on plasma membrane currents, Ca(2+) signaling, mitochondrial superoxide anion formation, and cell cycle progression were compared between irradiated (0-10 Gy) Bcl-2-overexpressing and empty vector-transfected Jurkat cells. As a result, IR stimulated a TRPM2-mediated Ca(2+)-entry, which was higher in Bcl-2-overexpressing than in control cells and which contributed to IR-induced G2/M cell cycle arrest. TRPM2 inhibition induced a release from G2/M arrest resulting in cell death. Collectively, this data suggests a pivotal function of TRPM2 in the DNA damage response of T cell leukemia cells. Apoptosis-resistant Bcl-2-overexpressing cells even can afford higher TRPM2 activity without risking a hazardous Ca(2+)-overload-induced mitochondrial superoxide anion formation.
authors.affiliation: Department of Radiation Oncology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Klumpp
authors.affiliation: Department of Radiation Oncology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Milan
authors.initials: M
authors.lastname: Misovic
authors.affiliation: Department of Physiology, University of Tübingen, 72076 Tübingen, Germany; Department of Oral & Maxillofacial Surgery, The University of Texas Health Science Center, San Antonio, TX 78229, USA.
authors.forename: Kalina
authors.initials: K
authors.lastname: Szteyn
authors.affiliation: Department of Physiology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Shumilina
authors.affiliation: Institute for Cell Biology (Cancer Research), University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Justine
authors.initials: J
authors.lastname: Rudner
authors.affiliation: Department of Radiation Oncology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Stephan M
authors.initials: SM
authors.lastname: Huber
mesh_terms: D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D018408:Patch-Clamp Techniques; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011839:Radiation, Ionizing; D015398:Signal Transduction; D013481:Superoxides / Q000737:chemistry; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: C000595707:BCL2 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D013481:Superoxides; D002118:Calcium
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