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: Dominik Klumpp, Milan Misovic, Kalina Szteyn, Ekaterina Shumilina, Justine Rudner, Stephan M Huber
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2016 Pg. 8026702 ( 2016) ISSN: 1942-0994 [Electronic] United States
• PMID: 26839633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCL2 protein, human
• Proto-Oncogene Proteins c-bcl-2
• TRPM Cation Channels
• TRPM2 protein, human
• Superoxides
• Calcium

Topics

• Apoptosis
• Calcium (metabolism)
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Cell Membrane (metabolism)
• Gene Expression Regulation, Leukemic
• Humans
• Jurkat Cells
• Leukemia, T-Cell (metabolism)
• Mitochondria (metabolism)
• Oxidative Stress
• Patch-Clamp Techniques
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Radiation, Ionizing
• Signal Transduction
• Superoxides (chemistry)
• TRPM Cation Channels (metabolism)