Independent transcriptional reprogramming and apoptosis induction by cisplatin.
Neither the molecular mechanisms whereby cancer cells intrinsically are or become resistant to the DNA-damaging agent cisplatin nor the signaling pathways that account for cisplatin cytotoxicity have thus far been characterized in detail. In an attempt to gain further insights into the molecular cascades elicited by cisplatin (leading to resistance or underpinning its antineoplastic properties), we comparatively investigated the ability of cisplatin, C2-ceramide and cadmium dichloride, alone or in the presence of an array of mitochondrion-protective agents, to trigger the permeabilization of purified mitochondria. In addition, we compared the transcriptional response triggered by cisplatin, C2-ceramide and cadmium dichloride in non-small cell lung carcinoma A549 cells. Finally, we assessed the capacity of cisplatin, C2-ceramide and cadmium dichloride to reduce the clonogenic potential of a battery of yeast strains lacking proteins involved in the regulation of cell death, DNA damage signaling and stress management. This multipronged experimental approach revealed that cisplatin elicits signaling pathways that are for the most part "private," i.e., that manifest limited overlap with the molecular cascades ignited by other inducers of mitochondrial apoptosis, and triggers apoptosis mainly in a transcription-independent fashion. Indeed, bona fide cisplatin-response modifiers that we have recently identified by a functional genome-wide siRNA screen are either not transcriptionally regulated during cisplatin-induced cell death or their transcriptional modulation reflects the activation of an adaptive response promoting cisplatin resistance.
Université Paris Descartes/Paris V, Sorbonne Paris Cité, Paris, France.
Lorenzo
L
Galluzzi
Ilio
I
Vitale
Laura
L
Senovilla
Tobias
T
Eisenberg
Didac
D
Carmona-Gutierrez
Erika
E
Vacchelli
Thomas
T
Robert
Hugues
H
Ripoche
Nora
N
Jägemann
Caroline
C
Paccard
Nicolas
N
Servant
Philippe
P
Hupé
Vladimir
V
Lazar
Philippe
P
Dessen
Emmanuel
E
Barillot
Hans
H
Zischka
Frank
F
Madeo
Guido
G
Kroemer
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D019256:Cadmium Chloride / Q000494:pharmacology; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000187:drug effects* / Q000235:genetics*; D002518:Ceramides / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D006801:Humans; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects*
D002518:Ceramides; D019256:Cadmium Chloride; D002945:Cisplatin