Jing K, Shin S, Jeong S, Kim S, Song K-S, Park J-H, Heo J-Y, Seo K-S, Park S-K, Kweon G-R, Wu T, Park J-I, Lim K
1] Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea [3] Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, China.
1] Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea.
Cell Death Dis. 2014 Nov 13;5(11):e1524. doi: 10.1038/cddis.2014.477.
The oncogenic human papillomavirus (HPV) E6/E7 proteins are essential for the onset and maintenance of HPV-associated malignancies. Here, we report that activation of the cellular ubiquitin-proteasome system (UPS) by the omega-3 fatty acid, docosahexaenoic acid (DHA), leads to proteasome-mediated degradation of E6/E7 viral proteins and the induction of apoptosis in HPV-infected cancer cells. The increases in UPS activity and degradation of E6/E7 oncoproteins were associated with DHA-induced overproduction of mitochondrial reactive oxygen species (ROS). Exogenous oxidative stress and pharmacological induction of mitochondrial ROS showed effects similar to those of DHA, and inhibition of ROS production abolished UPS activation, E6/E7 viral protein destabilization, and apoptosis. These findings identify a novel role for DHA in the regulation of UPS and viral proteins, and provide evidence for the use of DHA as a mechanistically unique anticancer agent for the chemoprevention and treatment of HPV-associated tumors.
致癌性人乳头瘤病毒（HPV）的E6/E7蛋白对于HPV相关恶性肿瘤的发生和维持至关重要。在此，我们报告称，ω-3脂肪酸二十二碳六烯酸（DHA）激活细胞泛素-蛋白酶体系统（UPS），导致蛋白酶体介导的E6/E7病毒蛋白降解，并诱导HPV感染的癌细胞凋亡。UPS活性的增加以及E6/E7癌蛋白的降解与DHA诱导的线粒体活性氧（ROS）过量产生有关。外源性氧化应激和线粒体ROS的药理学诱导显示出与DHA相似的效果，而抑制ROS产生则消除了UPS激活、E6/E7病毒蛋白不稳定和细胞凋亡。这些发现确定了DHA在UPS和病毒蛋白调节中的新作用，并为将DHA用作预防和治疗HPV相关肿瘤的具有独特作用机制的抗癌药物提供了证据。
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