Selective down-regulation of human papillomavirus transcription by 2-deoxyglucose.
The glycolytic pathway inhibitor 2-deoxyglucose (2-DG) is capable of suppressing the transcription of the human pathogenic papillomavirus type 18 (HPV 18) in cervical carcinoma cells and derived non-tumorigenic somatic cell hybrids at the level of transcription initiation. HPV down-regulation is selective, since other reference genes are not affected or even up-regulated under the same experimental conditions. Moreover, 2-DG appears to restore the normal half-life of the tumor suppressor gene product p53, because the protein is strongly up-regulated after HPV 18 E6/E7 suppression. The observed 2-DG-effect is not cytotoxic and is reversible after refeeding with fresh medium. HPV 18 suppression by 2-DG can be completely abrogated by simultaneous treatment with the intracellular Ca2+ antagonist TMB-8, indicating that Ca2+, a known intracellular "second messenger", is involved in this process. Elevated c-myc and p53 expression appears to be responsible for the time-dependent accumulation of apoptotic cells after prolonged 2-DG treatment. The finding that 2-DG acts selectively against the expression of a human pathogenic papillomavirus strongly suggests that an appropriate level of glycolysis is not only a peculiarity of growing tumors, but even may be an essential prerequisite for the maintenance of virus-specific E6/E7 gene expression. Our results may have substantial implications for the potential therapeutic application of 2-DG or other glucose derivatives in the treatment of precancerous and malignant HPV-associated lesions.
Maehama
T
T
Department of Obstetrics and Gynecology, School of Medicine, University of the Ryukyus, Japan.
Patzelt
A
A
Lengert
M
M
Hutter
K J
KJ
Kanazawa
K
K
Hausen
H
H
Rösl
F
F
D000255:Adenosine Triphosphate / Q000378:metabolism; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003470:Culture Media; D004268:DNA-Binding Proteins; D003847:Deoxyglucose / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000096:biosynthesis* / Q000235:genetics; D027383:Papillomaviridae / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D000998:Antiviral Agents; D002121:Calcium Channel Blockers; D003470:Culture Media; D004268:DNA-Binding Proteins; C052603:E6 protein, Human papillomavirus type 18; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D000255:Adenosine Triphosphate; D003847:Deoxyglucose