Mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that mediate intracellular signaling associated with a variety of cellular activities including cell proliferation, differentiation, survival, death, and transformation [1, 2]. The three main members that integrate the MAPK family in mammalian cells are stress-activated protein kinase c-Jun NH2-terminal kinase (JNK), stress-activated protein kinase 2 (SAPK2, p38), and the extracellular signal-regulated protein kinases (ERK1/2, p44/p42). ERK has a threonine-glutamic acid-tyrosine (Thr-Glu-Tyr) motif [79, 80] that plays a central role in stimulation of cell proliferation [81, 82]. The biological consequences of phosphorylation of ERK substrates include increased proliferation, differentiation, survival [83], angiogenesis [84], motility [85], and invasiveness [86]. The ERK pathway is triggered mainly by mitogens and cytokines (Figure 1), acting through receptor tyrosine kinases, G-protein-coupled receptors, and nonnuclear activated steroid hormone receptors [4, 65]. Most of the signals activating the ERK pathway are initiated through receptor-mediated activation of Ras [4] by stimulating the exchange of GDP bound to Ras for GTP [91]. Then, Ras phosphorylates Raf-1. Then, a MAPK cascade is initiated in which Raf-1 sequentially phosphorylates MEK1/2 and ERK1/2. Later, ERK1/2 translocate to the nucleus in a process that culminates in modulation of gene transcription through the activation of several transcription factors such as Ets-1 [4], ATF-2, c-Fos, c-Myc, Elk-1 [92], or NF-κB [29] (Figure 1). At the same time, ERK1/2 can also phosphorylate cytoplasmic and nuclear kinases, such as MNK1, MNK2, MPKAP-2, RSK, or MSK1 [90]. TGF-β and EGF are growth factors that can induce tumor progression by means of the ERK pathway [93–96]. Several studies showed that these factors are overexpressed in prostate cancer in comparison with normal tissue [95–98]. In different tumor cells, expression of some EGF family members such as EGF or TGF-α is associated with poor patient prognosis or resistance to chemotherapeutics [94–99]. IGF-1 and EGF stimulate intracellular signaling pathways converging at the level of ERK2 [100], which is a key kinase mediator of growth-factor-induced mitogenesis in prostate cancer cells [101]. The two major substrates of the IGF-1 receptor, insulin receptor substrate-1 [102] and Shc, are known to contribute to IGF-1-induced activation of ERK [103]. The ERK signaling pathway plays a role in several steps of tumor development [14]. In fact, some components of the Raf-MEK-ERK pathway are activated in solid tumors (such as prostate or breast cancer) and hematological malignances [104–106]. In approximately 30% of human breast cancers, mutations are found in the ERK1/2 MAPK pathway [65]. ERK1/2 and downstream ERK1/2 targets are hyperphosphorylated in a large subset of mammary tumors [107]. Mutations of K-Ras appear frequently in many cancers including those of the lung and colon [108]. Mutations in the B-Raf gene are responsible for 66% of malignant melanomas [109]. Increased expressions of Raf pathway has been associated with advanced prostate cancer, hormonal independence, metastasis, and a poor prognosis [110]. Moreover, prostate cancer cell lines isolated from patients with advanced cancer (LNCaP, PC3, DU145) expressed low levels of active Raf kinase inhibitors [105]. TNF-α acts as an ERK activator in some cases related to inflammation and cell proliferation. In this way, Ricote et al. [11] showed that ERK phosphorylation was notably increased by TNF-α in a dose-dependent manner in LNCaP cells. In prostate cancer, presence of Raf-1 and MEK1 in conjunction with elevated ERK1 and ERK2, and their phosphorylated forms, suggests that stimulation of cell proliferation could be triggered by IL-6 via the ERK pathway [104]. In fact, IL-6 expression increased in prostate cancer in comparison with normal tissue [104, 111]. Moreover, LNCaP cells which produce IL-6 show increased proliferation, at least in part, due to ERK activation [112]. Recently, a phase I clinical trial has revealed the ability of an anti-IL-6 antibody (siltuximab) to inhibit ERK1/2 phosphorylation in prostate tumors [113].

MAPK References