Docosahexaenoic acid induces the degradation of HPV E6/E7 oncoproteins by activating the ubiquitin-proteasome system.
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.
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.
K
K
Jing
1] Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea.
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S
Shin
1] Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea.
S
S
Jeong
1] Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea.
S
S
Kim
Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
K-S
KS
Song
Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
J-H
JH
Park
Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
J-Y
JY
Heo
Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
K-S
KS
Seo
Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
S-K
SK
Park
Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
G-R
GR
Kweon
Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
T
T
Wu
Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
J-I
JI
Park
1] Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea [3] Cancer Research Institute, Chungnam National University, Daejeon, Korea.
K
K
Lim
D000998:Antiviral Agents / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000187:drug effects / Q000502:physiology; D052161:Human papillomavirus 18 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
D000998:Antiviral Agents; D004268:DNA-Binding Proteins; C068651:E6 protein, Human papillomavirus type 16; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D017382:Reactive Oxygen Species; D012097:Repressor Proteins; D025801:Ubiquitin; C059731:oncogene protein E7, Human papillomavirus type 16; D004281:Docosahexaenoic Acids; D046988:Proteasome Endopeptidase Complex