Nongenomic Effects of Cisplatin: Acute Inhibition of Mechanosensitive Transporters and Channels without Actin Remodeling

N. Milosavljevic, C. Duranton, N. Djerbi, P. H. Puech, P. Gounon, D. Lagadic-Gossmann, M. T. Dimanche-Boitrel, C. Rauch, M. Tauc, L. Counillon, M. Poet
2010 Cancer Research  
Cisplatin is an antineoplastic drug, mostly documented to cause cell death through the formation of DNA adducts. In patients, it exhibits a range of short-term side effects that are unlikely to be related to its genomic action. As cisplatin has been shown to modify membrane properties in different cell systems, we investigated its effects on mechanosensitive ion transporters and channels. We show here that cisplatin is a noncompetitive inhibitor of the mechanosensitive Na + /H + exchanger
more » ... H + exchanger NHE-1, with a half-inhibition concentration of 30 μg/mL associated with a decrease in V max and Hill coefficient. We also showed that it blocks the Cl − and K + mechanosensitive channels VSORC and TREK-1 at similar concentrations. In contrast, the nonmechanosensitive Cl − and K + channels CFTR and TASK-1 and the Na + -coupled glucose transport, which share functional features with VSORC, TREK-1, and NHE-1, respectively, were insensitive to cisplatin. We next investigated whether cisplatin action was due to a direct effect on membrane or to cortical actin remodeling that would affect mechanosensors. Using scanning electron microscopy, in vivo actin labeling, and atomic force microscopy, we did not observe any modification of the Young's modulus and actin cytoskeleton for up to 60 and 120 μg/mL cisplatin, whereas these concentrations modified membrane morphology. Our results reveal a novel mechanism for cisplatin, which affects mechanosensitive channels and transporters involved in cell fate programs and/or expressed in mechanosensitive organs in which cisplatin elicits strong secondary effects, such as the inner ear or the peripheral nervous system. These results might constitute a common denominator to previously unrelated effects of this drug.
doi:10.1158/0008-5472.can-10-1253 pmid:20841472 fatcat:bkq6lp2u2bb5jjeouswxsenpma