The HPV E6/E7 Oncogenes: Key Factors for Viral Carcinogenesis and Therapeutic Targets. Issue 2 (February 2018)

• Record Type: Journal Article
• Authors: Hoppe-Seyler, Karin; Bossler, Felicitas; Braun, Julia A.; Herrmann, Anja L.; Hoppe-Seyler, Felix
• Is Part Of: Trends in microbiology. Volume 26:Issue 2(2018)
• Page Start: 158
• Page End: 168
• Publication Date: 2018-02
• Subjects: human papillomavirus -- senescence -- metabolism -- hypoxia -- mTOR -- therapy; Microbiology -- Periodicals; Infection -- Periodicals; Virulence (Microbiology) -- Periodicals; Infection -- Periodicals; Microbiology -- Periodicals; Virulence -- Periodicals; Microbiologie -- Périodiques; Infection -- Périodiques; Virulence (Microbiologie) -- Périodiques; Infection; Microbiology; Virulence (Microbiology); 579
• DOI: 10.1016/j.tim.2017.07.007
• Languages: English
• ISSNs: 0966-842X

Abstract

Abstract : Human papillomavirus (HPV)-induced cancers are expected to remain a major health problem worldwide for decades. The growth of HPV-positive cancer cells depends on the sustained expression of the viral E6 and E7 oncogenes which act in concert with still poorly defined cellular alterations. E6/E7 constitute attractive therapeutic targets since E6/E7 inhibition rapidly induces senescence in HPV-positive cancer cells. This cellular response is linked to the reconstitution of the antiproliferative p53 and pRb pathways, and to prosenescent mTOR signaling. Hypoxic HPV-positive cancer cells could be a major obstacle for treatment strategies targeting E6/E7 since they downregulate E6/E7 but evade senescence through hypoxia-induced mTOR impairment. Prospective E6/E7 inhibitors may therefore benefit from a combination with treatment strategies directed against hypoxic tumor cells. Trends: Despite the availability of prophylactic vaccines which protect against infection with oncogenic human papillomavirus (HPV) types, HPV-linked carcinogenesis is expected to remain an important health problem for decades to come. Targeting the viral E6/E7 oncogenes for functional inhibition should be an attractive therapeutic strategy to treat HPV-positive cancers with high specificity. Active mTOR signaling is critical to enable HPV-positive cancer cells to efficiently induce senescence in response to E6/E7 inhibition. Hypoxic HPV-positive cancer cells downregulate E6/E7 and evade senescence due to hypoxia-linked impairment of mTOR, posing a potential problem for the therapeutic efficacy of prospective E6/E7 inhibitors. Similar to chemotherapy and radiotherapy, therapeutic strategies aiming at E6/E7 inhibition could benefit from a combination with agents targeting hypoxic tumor cells.