MAPK signalling in cisplatin-induced death: predominant role of ERK1 over ERK2 in human hepatocellular carcinoma cells
Menée in vitro et in vivo, cette étude montre que, par rapport à la protéine ERK2, ERK1 joue un rôle prédominant dans la mort celullaire induite par un traitement au cisplatine d'un carcinome hépatocellulaire
Hepatocellular carcinoma treatment by arterial infusion of cisplatin exhibits certain therapeutic efficacy. However, optimizations are required and the mechanisms underlying cisplatin pro-apoptotic effect remain unclear. The mitogen-activated protein kinase (MAPK) pathway plays a key role in cell response to cisplatin and the functional specificity of the isoform MEK1/2 and ERK1/2 could influence this response. The individual contribution of each kinase on cisplatin-induced death was thus analysed after a transient or stable specific inhibition by RNA interference in the human hepatocellular carcinoma cells Huh-7 or in knock-out mice. We demonstrated here that ERK1 played a predominant role over ERK2 in cisplatin-induced death, whereas MEK1 and MEK2 acted in a redundant manner. Indeed, at clinically relevant concentrations of cisplatin, ERK1 silencing alone was sufficient to protect cells from cisplatin induced death both in vitro, in Huh-7 cells and ERK1-/- hepatocytes, and in vivo, in ERK1 deficient mice. Moreover, we showed that ERK1 activity correlated with the induction level of the pro-apoptotic BH3-only protein Noxa, a critical mediator of cisplatin toxicity. On the contrary, ERK2 inhibition up-regulated ERK1 activity, favoured Noxa induction and sensitized hepatocarcinoma cells to cisplatin. In conclusions, our results point to a crucial role of ERK1 in cisplatin-induced pro-apoptotic signal and lead us to propose that ERK2 specific targeting could improve the efficacy of cisplatin therapy by increasing ERK1 pro-death functions.
http://carcin.oxfordjournals.org/content/early/2012/10/01/carcin.bgs317.abstract