Pro-inflammatory cytokines and human prostate cancer
Rodriguez-Berriguete G., Fraile B., Paniagua R., Royuela M.
Cancer is a complex process in which cytokines are thought to play an important role. Cytokines are low-molecular weight soluble proteins that transmit signals between cells and are involved in several disorders. It has been well established that interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-α), named pro-inflammatory cytokines, play a key role in inflammatory processes by triggering activation of nuclear factor-kappa B (NF-kB). TNF-α can induce apoptosis through the intracellular signal transduction pathway involving the protein kinases TRAF-2 (integration point of apoptotic and survival signals), ASK1 (pro-apoptotic protein), MEK-4 (p38 activator and metastasis suppressor gene), JNK (stress mitogen activated protein kinase) and the transcription factor AP-1. TNF-α also induces cell proliferation either by p38 activation or when TRAF-2 simultaneously induces NIK-mediated activation of NF-kB. NIK and p38 may also be activated by IL-1. In fact, p38 activates several transcription factors, such as Elk-1, ATF-2 and NF-kB. The antitumor effects of TNF-α are mediated by inducing the expression of pro-apoptotic proteins, such as members of bcl-2 family as well as cell cycle inhibitors including p53 and p21. TNF-α also participates in oncogenesis and metastasis of different tissues. IL-1 is another physiological regulator of p38 and NIK which activates PAK-1by binding to two GTPases, called Cdc42 and Rac. These two molecules activate PAK-1, which in turn induces activation of MEK-6 and p38. IL-1 also activates NIK and stimulates IKK-β, which induces IkB-α degradation. IKK complex phosphorylates IkB, following its ubiquitination and rapid degradation, resulting in the nuclear translocation of NF-kB. This in turn, activates target genes involved in carcinogenesis: tumor initiation, malignant transformation and metastasis IL-6 exerts its effects through the membrane receptor complex composed of IL-6 receptor α (IL-6Rα) and glycoprotein 130 (gp130). The binding of IL-6 to IL-6Ra induces dimerization of gp130 and, subsequently, the activation of constitutively-associated gp130 Jak proteins. Jak proteins can simultaneously trigger functionally distinct and even opposing signaling pathways. One of the pathways leads to the activation of Ras by stimulating the exchange of Ras-bound GDP and GTP. Then, Ras initiates a MAPK cascade by sequential phosphorylation of Raf-1, MEK1/2 and ERK1/2 in a process that culminates in modulation of gene transcription through activation of several transcription factors, such as c-Myc, ATF-2, Elk-1 or NF-kB. The aim of this review is to elucidate the possible involvement of TNF-α/IL-1/IL-6 signal transduction pathways in the progression of prostate cancer and their role in altering the balance between apoptosis and cell proliferation. We will also discuss the importance of some components of the signaling pathways as potential therapeutic targets for prostate cancer. © 2012 by Nova Science Publishers, Inc. All rights reserved.