Nongenomic effects of cisplatin: acute inhibition of mechanosensitive transporters and channels without actin remodeling.
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 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.
Milosavljevic
Nina
N
Université de Nice Sophia Antipolis, Transport ionique: Aspects normaux et Pathologiques, CNRS UMR 6097, Faculté des Sciences, Nice, France.
Duranton
Christophe
C
Djerbi
Nadir
N
Puech
Pierre Henri
PH
Gounon
Pierre
P
Lagadic-Gossmann
Dominique
D
Dimanche-Boitrel
Marie Thérèse
MT
Rauch
Cyril
C
Tauc
Michel
M
Counillon
Laurent
L
Poët
Mallorie
M
D000199:Actins / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001696:Biomechanical Phenomena; D019556:COS Cells; D048430:Cell Shape / Q000187:drug effects; D002522:Chlorocebus aethiops; D002945:Cisplatin / Q000494:pharmacology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D018625:Microscopy, Atomic Force; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*
D000199:Actins; D000970:Antineoplastic Agents; D007473:Ion Channels; D009419:Nerve Tissue Proteins; D024683:Potassium Channels, Tandem Pore Domain; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; C103742:potassium channel protein TREK-1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C420132:potassium channel subfamily K member 3; D002945:Cisplatin