Abstract 2114: Docosahexaenoic acid induces degradation of human papillomavirus E6 and E7 oncoproteins through activation of the ROS-mediated ubiquitin-proteasome system in cervical cancer cells.

Sustained expression of high risk human papillomavirus (HR-HPV) E6/E7 oncogenes is essential for the maintenance of cervical cancer. We have previously reported that docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, triggers apoptosis in HR-HPV positive cervical cancer cells. The aim of present study was to investigate whether and how the DHA-induced apoptosis is associated with modulation of E6/E7 viral oncoproteins in HR-HPV positive HeLa and SiHa cells. We found that DHA diminished E6/E7 protein levels in a time-dependent manner and restored the function of known E6/E7 binding targets, p53 and retinoblastoma (Rb) tumor suppressors. DHA increased the ubiquitination and proteasomal degradation of E6/E7 oncoproteins as well as three different ubiquitin-proteasome system (UPS) reporter substrates (GFP-CL1, GFP-ODC and UbG76V-GFP), supporting that DHA degrades E6/E7 viral proteins via the UPS. Using HeLa cells constitutively expressing UbG76V-GFP reporter, we confirmed these effects of DHA and further observed that similar to DHA, hydrogen peroxide (H2O2) was also able to accelerate E6/E7 degradation through promoting the UPS activity. In addition, reactive oxygen species (ROS) scavengers significantly prevented the UPS-mediated reduction in E6/E7 viral proteins and apoptosis caused by DHA and H2O2, suggesting that the augmented UPS activity and E6/E7 degradation caused by DHA depend on its effect on ROS generation. Together, our results show that DHA induces degradation of HPV E6/E7 oncoproteins through activation of the ROS-mediated UPS, and provide novel insights into the mechanism by which DHA exerts its inhibitory effect on virus-associated cancer. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by Korea government (2012-0005767, 2012-0005456 and 2011-0003060)]. Citation Format: Kaipeng Jing, Soyeon Shin, Soyeon Jeong, Ji-Hoon Park, Kang-Sik Seo, Jun-Young Heo, Jeongsu Han, Jong-Il Park, Gi-Ryang Kweon, Seung-Kiel Park, Wan-Hee Yoon, Byung-Doo Hwang, Kyu Lim. Docosahexaenoic acid induces degradation of human papillomavirus E6 and E7 oncoproteins through activation of the ROS-mediated ubiquitin-proteasome system in cervical cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2114. doi:10.1158/1538-7445.AM2013-2114