Inflammatory Signaling Involved in High-Fat Diet Induced Prostate Diseases

Abstract

High-Fat Diet (HFD) has emerged as an important risk factor not only for obesity and diabetes but also for urological disorders. Recent research provides ample evidence that HFD is a putative cause for prostatic diseases including prostate cancer. The mechanisms whereby these diseases develop in the prostate have not been fully elucidated. In this review we discuss signaling pathways intricately involved in HFD-induced prostate disease. We performed a search through PUBMED using key words "high fat diet" and "prostate". Our data and perspectives are included in this review along with research performed by various other groups. HFD is positively associated with an increased risk of benign prostatic hyperplasia (BPH) and prostate cancer. HFD induces oxidative stress and inflammation in the prostate gland, and these adverse influences transform it from a normal to a diseased state. Studies demonstrate that HFD accelerates the generation of reactive oxygen species by driving the NADPH oxidase system, exacerbating oxidative stress in the prostate. HFD also causes a significant increase in the levels of pro-inflammatory cytokines and gene products through activation of two important signaling pathways: the Signal Transducer and Activator of Transcription (STAT)-3 and Nuclear Factor-kappa B (NF-κB). Both these pathways function as transcription factors required for regulating genes involved in proliferation, survival, angiogenesis, invasion and inflammation. The crosstalk between these two pathways enhances their regulatory function. Through its influences on the NF-κB and Stat-3 signaling pathways, it appears likely that HFD increases the risk of development of BPH and prostate cancer.

Keywords: Benign prostatic hyperplasia; NADPH oxidase; Nuclear factor-kappa B; Signal transducer and activator of transcription; prostate cancer.

Figure 1

High-fat diet (HFD) is a key cause for benign prostatic hyperplasia, lower urinary tract symptom and cancer in men. The consequence of HFD-induced obesity leads to prostate diseases observed at various levels. 1) Adeponectin, involved in the regulation of glucose levels and fatty acid breakdown is deregulated by HFD contributing to obesity. 2) HFD causes alterations of receptors and growth factors such as IGFR-1, IL-6 and plasma insulin leading to type 2 diabetes. 3) Upstream kinases such as PKCε and Akt/PKB are constitutively activated by these receptors and growth factors that in turn activate transcription factors, Stat-3 and NF-ҡB initiating pro-inflammatory signaling pathways. 4) These transcription factors translocate into the nucleus and initiate transcription of several genes (iNOS, COX-2, TNFα, Bcl-X_L, Bcl-2, IL-1β, IL-6) responsible for cell proliferation, inflammation and cell survival. The crosstalk between Stat-3 and NF-ҡB sustain pro-inflammatory signals and enhance disease progression. ↑ denotes upregulation, ↓ denotes downregulation, ↔ denotes crosstalk, and dotted arrow denotes feedback regulation.