Abstract 2515: Inverse relationship between PSA and IL-8 in prostate cancer: An insight into the mechanisms of NF-κB-mediated radioresistance

Abstract

Abstract Nuclear factor κB (NF-κB), an inflammatory responsive transcription factor, is involved in tumorigenesis and resistance of cancer cells to therapy-induced cytotoxicity. Our previous studies demonstrated that activation of RelB-mediated NF-κB alternative pathway contributes to tumorigenicity of prostate cancer, decreased the circulating levels of prostate specific antigen (PSA), and enhanced the level of interleukin-8 (IL-8). The present study extends to directly test the role of RelB on radioresistance of prostate cancer in vivo, investigate the relationship between IL8 and PSA expression, and determine their role in the response of prostate cancer to radiation. We found that expression of RelB in prostate cancer cells with a low basal level of RelB (LNCaP) reduced their radiosensitivity and suppression of RelB in prostate cancer cells with a high basal level of RelB (PC3) enhanced their radiosensitivity in vitro and in xenograft tumors. The RelB-mediated inverse relationship between PSA and IL-8 expression was verified through direct modulation of RelB levels by transfection of RelB cDNA and RNAi in multiple prostate cancer cell lines. Interestingly, when the cellular levels of PSA and IL-8 were manipulated, by treating cultural cells with pure compounds or genetic manipulations, we found that up-regulation of IL-8 with concurrent down-regulation of PSA reduced radiosensitivity of prostate cancer cells. In contrast, up-regulation of PSA with concurrence down-regulation of IL-8 resulted in an increase in radiosensitivity. Together, the results reveal a previously unrecognized role of IL-8 on PSA expression, identify an inverse relationship between PSA and IL-8 as an indicator of radiosensitivity and implicate inhibition of the NF-κB alterative pathway as a promising approach for prostate cancer treatment. 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 2515. doi:10.1158/1538-7445.AM2011-2515