Figure 1.

Mechanisms of extracellular signal-regulated kinase (ERK)-induced chemoresistance. The RAS/RAF/MEK/ERK axis [rat sarcoma 2 viral oncogene homolog/rapidly accelerated fibrosarcoma/mitogen-activated protein kinases (MAPK)-extracelluar signal-regulated kinase], upon the activation of tyrosine kinase receptors (TKR) by growth factors (GFs), cytokines, or cell–extracellular matrix (ECM) interaction, cooperates with phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), c-Jun amino-terminal kinase (JNK), steroid receptor coactivator-1 (Src)/Aurora kinase, glycogen synthase kinase 3-β (GSK-3β)/β-catenin signals, activating a pool of transcription factors that determine: (i) increased cell proliferation by up-regulating cyclins and cyclin-dependent kinase (CDKs) and/or down-regulating the cell cycle check-points p21 and p27; (ii) prevention of apoptosis by decreasing Bcl-2 proteins, reducing mitochondrial reactive oxygen species (ROS) and mitochondrial fission; (iii) increased expression and activity of drug efflux transporters, such as P-glycoprotein (Pgp), multidrug resistance related proteins (MRPs), and breast cancer resistance proteins (BCRP). All these mechanisms make a tumor cell more resistant to chemotherapy. Green arrows: apotosis-related mechanisms; red arrow: pro-survival-related mechanisms.