Abstract 2164: High fat diet-induced intraprostatic inflammation involves association between Stat-3 and NF-kappaB: Role in pathogenesis of prostate cancer

Abstract

Abstract Western style high-fat diet (HFD) is a risk factor for obesity, diabetes, and cancer. In our previous studies we have demonstrated that HFD increases oxidative stress and inflammation in the prostate of NF-kappaB-luciferase transgenic reporter mice (Vykhovanets et al., Prostate 2010). However, the molecular mechanism(s) underlying HFD-induced inflammation in the prostate largely remains unknown. Signal transducer and activator of transcription (Stat-3) and nuclear factor-kappa B are the important signaling pathways that are activated during inflammation. The pro-inflammatory cytokines induced are the transcriptional targets of Stat-3 and NF-kappaB and are known to be involved in their activation. We examined the role of HFD in increasing the nuclear activation of Stat-3 and NF-kappaB and the mechanism(s) involved leading to inflammation of the prostrate. Male 16 week old C57BL/6J mice were either fed with regular diet (RD) or HFD for 4 and 8 weeks. The animals were sacrificed at the end of each time period. HFD intake caused significant increase in the plasma levels of IL-6 and IL-17, after 4 weeks of feeding that further increased after 8 weeks, compared to mice fed with RD. These cytokines have been reported to induce Stat-3. HFD intake also caused marked increase in the levels of IL-1beta and TNFalpha which are known activators of NF-kappaB. A significant increase in the levels of PKCepsilon was observed after 4 weeks of HFD feeding in these mice. Elevated levels of PDK1 and p-Akt (Ser473) were observed in the prostate tissues of HFD group. Increase in the levels of kinases corroborated with the nuclear translocation of Stat-3 and NF-kappaB/p65/RelA with significantly increased expression of Tyr705, Ser727 Stat-3 and Ser536 p65/RelA in the prostrate of HFD mice. An association between Ser727 Stat-3 and Ser 536 p65/RelA was observed in the nucleus of prostate tissue of HFD group. Furthermore, increased DNA binding of p65/RelA and Stat-3 as well as their association was observed in HFD group. Taken together, HFD increases inflammation in the prostate through activation of Stat-3 and NF-kappaB and their association may play a key role in the pathogenesis of prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2164. doi:10.1158/1538-7445.AM2011-2164