Selective down‐regulation of human papillomavirus transcription by 2‐deoxyglucose

• Published in: International journal of cancer 1998-05, Vol.76 (5), p.639-646
• Main Authors: Maehama, Toshiyuki, Patzelt, Andrea, Lengert, Maike, Hutter, Karl‐Josef, Kanazawa, Koji, Zur Hausen, Harald, Rösl, Frank
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Antiviral Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Calcium Channel Blockers - pharmacology; Culture Media; Deoxyglucose - pharmacology; DNA-Binding Proteins; Down-Regulation - drug effects; Female genital diseases; Gallic Acid - analogs & derivatives; Gallic Acid - pharmacology; Gene Expression Regulation, Viral - drug effects; Gynecology. Andrology. Obstetrics; HeLa Cells; Human papillomavirus 18; Humans; Medical sciences; Oncogene Proteins, Viral - biosynthesis; Oncogene Proteins, Viral - genetics; Papillomaviridae - drug effects; Papillomaviridae - genetics; Papillomaviridae - metabolism; RNA, Messenger - metabolism; Transcription, Genetic - drug effects; Tumor Suppressor Protein p53 - biosynthesis; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/(SICI)1097-0215(19980529)76:5<639::AID-IJC5>3.0.CO;2-R

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 HPV18 E6/E7 suppression. The observed 2‐DG‐effect is not cytotoxic and is reversible after refeeding with fresh medium. HPV18 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 pecularity 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. Int. J. Cancer 76:000–000, 1998.© 1998 Wiley‐Liss, Inc.