Docosahexaenoic acid induces the degradation of HPV E6/E7 oncoproteins by activating the ubiquitin-proteasome system

K Jing; S Shin; S Jeong; S Kim; K-S Song; J-H Park; J-Y Heo; K-S Seo; S-K Park; G-R Kweon; T Wu; J-I Park; K Lim

doi:10.1038/cddis.2014.477

Docosahexaenoic acid induces the degradation of HPV E6/E7 oncoproteins by activating the ubiquitin-proteasome system

Cell Death Dis. 2014 Nov 13;5(11):e1524. doi: 10.1038/cddis.2014.477.

Authors

K Jing¹, S Shin², S Jeong², S Kim², K-S Song³, J-H Park³, J-Y Heo³, K-S Seo³, S-K Park³, G-R Kweon³, T Wu⁴, J-I Park³, K Lim⁵

Affiliations

¹ 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.
² 1] Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea [2] Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea.
³ Department of Biochemistry, School of Medicine, Chungnam National University, Daejeon, Korea.
⁴ Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA.
⁵ 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.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antiviral Agents / pharmacology*
DNA-Binding Proteins / metabolism*
Docosahexaenoic Acids / pharmacology*
Enzyme Activation / drug effects
Gene Expression Regulation
HeLa Cells
Host-Pathogen Interactions
Human papillomavirus 16 / drug effects
Human papillomavirus 16 / physiology
Human papillomavirus 18 / drug effects
Human papillomavirus 18 / physiology
Humans
Oncogene Proteins, Viral / metabolism*
Papillomavirus E7 Proteins / metabolism*
Proteasome Endopeptidase Complex / drug effects
Proteasome Endopeptidase Complex / metabolism
Proteolysis / drug effects
Reactive Oxygen Species / agonists
Reactive Oxygen Species / metabolism
Repressor Proteins / metabolism*
Signal Transduction
Ubiquitin / genetics
Ubiquitin / metabolism
Ubiquitination / drug effects

Substances

Antiviral Agents
DNA-Binding Proteins
E6 protein, Human papillomavirus type 16
E6 protein, Human papillomavirus type 18
E7 protein, Human papillomavirus type 18
Oncogene Proteins, Viral
Papillomavirus E7 Proteins
Reactive Oxygen Species
Repressor Proteins
Ubiquitin
oncogene protein E7, Human papillomavirus type 16
Docosahexaenoic Acids
Proteasome Endopeptidase Complex