Effects of Diacerein on cells expressing HPV oncogenes

• Grant number: 21/11887-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: June 01, 2022
• End date: December 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Enrique Mario Boccardo Pierulivo
• Grantee: Raquel Rodrigues Loiola
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

HPV is the etiologic agent of cervical cancer, which causes the death of over a quarter million women every year worldwide. HPV types classified as high-oncogenic risk are responsible for the great majority of the cases. In order to establish a productive infection HPV has to evade the protective mechanisms of the host cell, such as autophagy and the innate immune response. Three viral proteins are critical in this process: E5, E6 and E7. These factors interfere in the formation of the phagosome and expression of TLRs. Persistent HPV infection causes chronic inflammation, which, together with the genomic instability resultant from sustained E6 and E7 expression, may favor the integration of HPV DNA in the host genome, an important step in HPV-mediated carcinogenesis. HPV oncoproteins are associated with the activation of the transcription factor NF-kB, promoting the progression of the cell cycle and up-regulation of COX-2. Besides, E6 and E7 interfere with the expression and function of elements of the extracellular matrix (ECM), including the expression of some matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9. This is achieved, in part, through the down-regulation of RECK and up-regulation of COX-2, favoring tumor establishment. Therefore, the use of non-steroidal anti-inflammatory drugs (NSAIDs) that inhibit COX-2 may represent a valid strategy to prevent the progression of HPV- related pathologies. In this study we aim to determine the effect of diacerein in cells that express HPV oncogenes. Diacerein is a NSAID used in the treatment of osteoarthritis and shown to retard the progression of different tumor types through inhibition of NF-kB. We will address the effect of this drug on the induction of autophagy and the expression/activity of ECM components.