Activation of mitogen-activated protein kinases by cisplatin and their role in cisplatin-resistance

Abstract

Mitogen-activated protein kinases (MAPKs) are critical components of a complex intracellular signalling network that ultimately regulates gene expression in response to a variety of extracellular stimuli. By transducing the signals from the cell surface to the nucleus and activating there gene expression, MAPKs control cell proliferation, differentiation and cell death. In mammalian cells there are three major pathways of MAPKs: stress-activated protein kinase/c-Jun-N-terminal kinase (SAPK/JNK), p38 kinase and extracellular signal-regulated kinase (ERK). Generally, SAPK/JNK and p38 are key mediators of stress and inflammation responses evoked by a variety of physical, chemical and biological stress stimuli, while ERK 1/2 cascade is mostly induced by growth factors. The importance of MAPKs activation in cell response to cis-diamminedichloroplatinum(II) (cisplatin; cDDP) and resistance development to this anti-cancer drug has been gradually appreciated in recent years. Today it is believed that MAPK activation is a major component deciding the cell fate in response to cisplatin. Their role in response to cisplatin is complex as these proteins, in most cases, are able to induce apoptosis, but also suppress it or have no role in this process. The final decision depends on the cell type, as well as proliferation and differentiation status of tumour cells. This review summarises current knowledge concerning the role of MAPK family members in cell response to cDDP, as well as their role in cisplatin-resistance.