The Pathologic Role of Toll-Like Receptor 4 in Prostate Cancer

Abstract

Toll-like receptor (TLR) 4 is expressed on normal and malignant prostate epithelial cells. The TLR4 and its downstream signaling pathways mediate innate immune responses in the host against invading pathogens. However, multiple lines of evidence shows that TLR4 expression is increased in prostate tissues from prostate cancer patients, and altered TLR4 signals may promote cancer development, as well as antitumor effects. In this review, we have summarized key features of the TLR4 signaling pathway and its associated immune responses and focused on the pathologic role of TLR4 in prostate carcinogenesis and tumor progression.

Keywords: bacteria; carcinogens; inflammation; prostate cancer; toll-like receptor 4.

Figure 1

Toll-like receptor (TLR) 4 signaling pathway. TLR4 signaling pathway can be regulated by MyD88-dependent and MyD88-independent pathways. Upon the activation of MyD88, IL-1 receptor-associated kinase (IRAK) and tumor necrosis factor-receptor-associated factor 6 (TRAF6) are recruited to lead to degradation of IKKβ and disinhibition of NF-κB, which results in pro-inflammatory cytokine production (e.g., TNF-α and IL-6). The MyD88 pathway signals also activate MAKP and extracellular signal-regulated kinase (ERK) through TRAF6, which results in AP-1 activation. The MyD88-independent pathway is TRIF dependent. Upon the activation of TRIF-related adaptor molecule (TRAM)/TRIF, TRAFs are recruited, which leads to interferon regulatory factor 3 (IRF3) activation and type I IFN production.