Oxaliplatin-induced mitochondrial apoptotic response of colon carcinoma cells does not require nuclear DNA.
We previously established a model of acquired oxaliplatin resistance derived from the HCT116 oxaliplatin-sensitive cell line (HCT116S) and consisting in two resistant clones (HCT116R1, HCT116R2) and their total or partial revertants (HCT116Rev1 and HCT116Rev2, respectively). Using this cellular model, we explored the contribution of mitochondrial apoptosis and nuclear DNA to oxaliplatin-mediated apoptosis induction and oxaliplatin resistance. We showed that the activity of oxaliplatin is mediated by the induction of Bax/Bak-dependent mitochondrial apoptosis and that oxaliplatin resistance is mediated by a defect in Bax/Bak activation correlating with a reduced loss of the mitochondrial transmembrane potential (DeltaPsim). In addition, we observed that p53 only contributed marginally to oxaliplatin-induced cytotoxicity and was not involved in oxaliplatin resistance. Moreover and surprisingly, depletion of the nucleus in HCT116S cells did not abolish the oxaliplatin-induced DeltaPsim loss indicative of imminent apoptosis. Enucleation abolished the oxaliplatin resistance of HCT116R1 cells, while HCT116R2 cytoplasts conserved their resistant phenotype. Altogether, these data demonstrate that oxaliplatin exerts its cytotoxic effects by inducing mitochondrial apoptosis and that these effects can be initiated by interacting on other cellular structures than nuclear DNA. Resistance to oxaliplatin may imply both nuclear and cytoplasmic compartments.
Gourdier
Isabelle
I
CNRS-UMR 8125, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille-Desmoulins, F-94805 Villejuif, France.
Crabbe
Laure
L
Andreau
Karine
K
Pau
Bernard
B
Kroemer
Guido
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D004247:DNA / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D004247:DNA